Ex Parte 7612181 et al

Patent Trials and Appeals Board

Mar 21, 2014

95001380 - (S) (P.T.A.B. Mar. 21, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 95/001,380 06/24/2010 7612181 ABT-110.2 USRX 4816 74943 7590 04/03/2017 YANKWICH & ASSOCIATES, P.C. (AND ABBVIE BIORESEARCH CENTER) 201 BROADWAY CAMBRIDGE, MA 02139 EXAMINER TURNER, SHARON L ART UNIT PAPER NUMBER 3991 MAIL DATE DELIVERY MODE 04/03/2017 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ SANOFI-AVENTIS, SA Requester and Appellant v. ABBOTT LABORATORIES Patent Owner and Respondent ____________ Appeal 2017-001183 Reexamination Control 95/001,380 Patent 7,612,181 B2 Technology Center 3900 ____________ Before JAMES T. MOORE, RICHARD M. LEBOVITZ, and RAE LYNN GUEST, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION UNDER § 41.77(f) This is a final decision under 37 C.F.R. § 41.77(f). The above- identified inter partes reexamination of U.S. Patent No. 7,612,181 B2 (“the ’181 patent) was decided by the Patent Trial and Appeal Board Decision on March 24, 2014 (“Decision” or “Dec.”). In the Decision, the Examiner’s determination not to adopt Rejections 2 and 3 of claims 1-3, 5-7, 31, and 32 under 35 U.S.C. § 103(a) was reversed. A reversal of an Examiner’s Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 2 determination not to adopt a rejection constitutes a new ground of rejection. See 37 C.F.R. § 41.77(b). Patent Owner (“Abbott”) requested that prosecution be re-opened under 37 C.F.R. § 41.77(b)(1). The Request included new evidence from Abbott constituting a second declaration under 37 C.F.R. § 1.132 by Dr. Roland Kontermann (“Kontermann 2 Decl.”) and a declaration by Dr. Janice Reichert (“Reichert Decl.”). The Declarations were entered and the Request to Reopen Prosecution granted. Order Granting Request to Reopen Prosecution and Remand to Examiner (“Order”; mailed Nov. 20, 2014). Requester (“Sanofi”) filed comments under 37 C.F.R. § 41.77(c) (“Sanofi 41.77c Comments”) accompanied by new evidence constituting a second declaration of Drs. Davis and Verhoeyen (“Davis-Verhoeyen 2 Decl.”). Upon remand to the Examiner, the Examiner made a determination under 37 C.F.R. § 41.77(d) (“Determination”; mailed June 2, 2015) upholding the Board’s Decision to reinstate Rejections 2 and 3. Abbott filed comments under § 41.77(e) on the Examiner’s determination (“Abbott 41.77e Comments”). Sanofi filed comments after the Examiner’s determination under § 41.77(e) (“Sanofi 41.77e Comments”). The appeal has now been returned to the Board for a final decision under 37 C.F.R. § 41.77(f). After considering the entirety of the evidence before us, we have concluded that a preponderance of the evidence does not support the obviousness of the claimed subject matter as set forth in Rejections 2 and 3. As explained in more detail below, this conclusion is based on the lack of a reason to have utilized the CH1-CL2 domain in the claimed engineered Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 3 antibody to have arrived at the claimed structure. Specifically, Dr. Kontermann in his second declaration identified a misunderstanding in the Decision which merited reconsideration of the evidence and the conclusions based upon it. CLAIM 1 The claimed subject matter is directed to a binding protein comprised of four polypeptide chains and four functional antigen binding sites. An exemplary embodiment is DVD-Ig (Dual Variable Domain) which is depicted below: DVD-Ig is reproduced above. The heavy shaded lines represent heavy chains; the lighter shaded lines represent light chains. Vb and Va are variable domains, each capable of having a different antigen binding specificity and each composed of a heavy and light chain. When the antigen specificities of Vb and Va are different, the binding protein (also referred to herein as an antibody) is “bispecific” because it is specific for two different antigens. CH1 and CL are constant domains comprising heavy and light chains, respectively. CH2 and CH3 are constant domains that comprise only heavy chains and which are identified as an antibody “Fc” region. The Fc Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 4 portion of an antibody mediates several effector functions, such as cytokine induction and complement-dependent cytotoxicity. ’181 patent, col. 17, ll. 26-30. As shown in the figure reproduced above, the heavy chains are on one peptide and the light chains are on another shorter peptide. The heavy and light chains are, therefore, “segregated” from each other. Bispecific antibodies were known in the prior art (’181 patent, cols. 1-3). Bispecific antibodies are described in the ’181 patent as useful to treat cancer, inflammatory conditions, and other diseases (id. at col. 1, 14-17). Claim 1, the only independent claim on appeal, reads as follows (bracketed letters [A] and [B] have been added to highlight the two different polypeptides; indentations and paragraph breaks have been added to clarify the composition of each polypeptide): 1. A binding protein comprising four polypeptide chains, [A] wherein two polypeptide chains comprise VD1- (X1)n-VD2-C-(X2)n, wherein VD1 is a first heavy chain variable domain, VD2 is a second heavy chain variable domain, C is a heavy chain constant domain, X1 is a linker with the proviso that it is not CH1, and X2 is an Fc region; and [B] two polypeptide chains comprise VD1-(X1)n-VD2- C-(X2)n, wherein VD1 is a first light chain variable domain, VD2 is a second light chain variable domain, C is a light chain constant domain, X1 is a linker with the proviso that it is not CH1, and X2 does not comprise an Fc region; and n is 0 or 1; wherein said four polypeptide chains of said binding protein form four functional antigen binding sites. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 5 The polypeptides labeled as [A] comprise the heavy chains. When X2 is 1, the binding protein has an Fc domain. When X2 is 0 for polypeptide [A], the binding protein lacks an Fc region. The polypeptide labeled as [B] comprises the light chains. [A] and [B] assemble to form four functional antigen binding sites. The latter are shown above in DVD-Ig, reproduced above, as two VA binding sites and two VB binding sites. The claim does not require VA and VB to bind to different antigens and thus are not limited to bispecific antibodies. Rejections 2 and 3 focused on the embodiment in which the claimed binding protein comprises the Fc region in which VA and VB bind to different antigen targets. Both Abbott and Sanofi addressed this embodiment in their briefings. REJECTIONS The following two rejections were adopted in the Decision. The full citations to the publications can be found in the Decision and are not repeated here. 2. Claim 1-3, 5-7, 31, and 32 of the ’181 patent as obvious under 35 U.S.C. § 103(a) in view of the ’830 patent, Müller, and Lu 2005. 3. Claim 1-3, 5-7, 31, and 32 of the ’181 patent as obvious under 35 U.S.C. § 103(a) in view of the ’830 patent, Miller (2003), Müller, Lu (2005), Lu (2003), Lu (2004), and Zuo (2000). CH1-CHL Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 6 Claim 1 comprises [A] a heavy chain comprising the VD1 and VD2 heavy chain domains with a heavy chain constant domain C joined to heavy chain VD2 (VD1-VD2-C heavy); and [B] a light chain comprising the VD1 and VD2 light chain domains with a light chain constant domain C joined to light chain VD2 (VD1-VD2-C light). The prior art heavy chain constant domain C and light chain constant domain C are referred to as CH1 and CL, respectively. Since the CH1 and CL domains pair with each other, they are referred to collectively throughout this decision as CH1-CL. The CH1-CL domains are depicted in DVD-Ig reproduced above as attached to the heavy and light variable domains Va. In the Decision, we discussed the CH1-CL domains as follows: With respect to the inclusion of the CH1-CL domains in the claimed binding protein, Dr. Kontermann acknowledged that Müller utilized such domains and that this “approach can also be used to produce tetravalent IgG-like constructs as described in Lu (2004) and Zuo [(]2000[)].” (Kontermann [1] Decl. ¶ 56). Thus, Dr. Kontermann does not appear to dispute the obviousness of utilizing a CH1-CL domain to have made the claimed binding protein. However, Dr. Kontermann’s argues that the latter publications teach that crossing-over does not occur when CH1-CL is fused to scFv [single chain variable antigen fragment] units and thus the skilled worker would not had reason to have made the claimed configuration with CH1- CL attached to both the heavy and light chain (id. at ¶¶ 56-57). Dr. Kontermann’s testimony is speculative since both Zuo [(]2000[)] and Lu [(]2004[)] utilized CH1-CL domains for each of the scFv binding sites. Dec. 18. Dr. Kontermann responded in his Declaration prepared after the Decision that his “prior testimony has been misunderstood.” Kontermann 2 Decl. ¶ 42. Dr. Kontermann clarified that the Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 7 paragraph in his first Declaration cited in the Decision referred to the use of CH1-CL to hold two separate scFv binding units together of different specificities. Kontermann 2 Decl. ¶ 42; Kontermann 1 Decl. ¶ 56. A scFv is antibody binding domain made of a VH and VL domain linked by a flexible peptide. Kontermann 2 Decl. ¶ 32. In contrast, Dr. Kontermann explained that the CH1-CL domain in the claimed antibody is used to pair the light and heavy chains of a single antigen binding site, as shown in the DVD-Ig reproduced above. Kontermann 1 Decl. ¶ 56. Dr. Kontermann also pointed out that paragraph 42 in his second declaration explained that the results of Lu (2004) and Zuo (2000) teach “that two different chains composed of complementary variable domains (VH-VL in the examples) are not expected to reliably pair when fused to a CH1 and CL domain or to a Fe region.” Kontermann 2 Decl. ¶ 42. We agree with Dr. Kontermann that we erred in stating that “Dr. Kontermann does not appear to dispute the obviousness of utilizing a CH1-CL domain to have made the claimed binding protein.” Dec. 18. As discussed in more detail below, upon reconsideration in view of the additional evidence adduced during the return to prosecution, we find that the evidence does not support the obviousness of utilizing a CH1-CL domain to have made the claimed binding protein having a VD1- VD2-CH1 heavy chain and a VD1-VD2-CL light chain. DISCUSSION The claimed binding protein comprises [A] a heavy chain with two variable heavy chain domains linked together and [B] a light chain with two Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 8 variable light chain domains linked together. Chains [A] and [B] pair to form to functional antigen binding domains. The light and heavy chains are segregated from each other. The ’830 patent is cited in Rejections 2 and 3 for its teaching of variable light domains (VL) and variable heavy domains (VH) on separate chains which associate to form two antigen binding sites, the same configuration recited in the claimed antibody and as depicted in the drawing of DVD-Ig reproduced above.1 This configuration is reproduced below and is referred to as the “double head complex”: 1 The configuration of the ’830 patent, with the light and heavy domains segregated from each other, is mentioned in several of the publications cited by Abbott as praising the claimed invention. For example, Presta (2008) wrote: “An elegant solution to the problem was reported recently in which one VL domain was fused at its C-terminus to the N-terminal portion of a second, different VL domain (i.e.[,] VL1-VL2-CL) and the partner VH1 domain fused in a similar manner to VH2 (i.e.[,] VH1-VH2-CH1).” Presta 468. We note that, while Presta clearly praised the configuration described in the ’830 patent, Presta additionally describes the CH1-CL domains as part of the construct, domains which are not described in the ’830 patent. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 9 The drawing above, reproduced from the ’830 patent, shows a double head antibody fragment (middle drawing) comprised of two variable light chain domains joined together (leftmost drawing) and two variable heavy chains joined together (rightmost drawing). When the separate chains associate, they form a double-head antibody with two functional antigen binding sites as in claim 1 of this appeal. The double-head antibody fragment of the ’830 patent lacks 1) CH1- CL domains, with CH1 added to a heavy chain and CL added to a light chain; and 2) the optional constant region CH2/CH3. To meet this deficiency, Miller (2003), Müller, Lu (2005), Lu (2003), Lu (2004), and Zuo (2000) were cited. Miller (2003), Müller, Lu (2004), and Zuo (2000) describe constructs with the CH1-CL domains. Lu (2003) and Lu (2005) describe constructs with the CH3 and CH2/CH3 domains, respectively. Dec. 8, 10. The discussion below focuses on the cited prior art publications which teach CH1-CL in an engineered antibody construct. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 10 Zuo (2000) and Lu (2004) Each of Zuo (2000) and Lu (2004) show the same basic antibody configuration: 1) single chain antibodies formed by a single chain comprising the light and heavy chains fused together (“scFv”) to form an antigen binding site (two constructs have four scFv antigen binding sites and one construct has two scFv binding sites); and 2) the CH1-CL constant region which dimerizes two single chain scFV antibodies together. The claimed antibody, as exemplified by DVD-Ig, however, does not use the CH1-CL region to dimerize two antigen binding sites together as in Zuo (2000) and Lu (2004), but instead uses the CH1-CL region to pair the heavy and light chains of Vb-Va together. Lu (2004) and Zuo (2000) do not teach utilizing the CH1-CL domain to pair heavy and light chains together (i.e., a VH-CH1/VL-CL structure). Instead, Lu (2004) and Zuo (2000) teach dimerizing two antigen binding units, each of which comprising both a heavy and light chain (i.e., a VH-VL- CH1/VH-VL-CL structure). Neither the Examiner nor Sanofi articulated an adequate reason that would have led the skilled worker at the time of the invention to modify the CH1-CL domain in Zuo (2000) and Lu (2004) to pair the light and heavy chains together instead of dimerizing two different antigen binding sites. To illustrate this difference, the drawings from Lu (2004) and Zuo (2000) are reproduced below, along with DVD-Ig. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 11 As shown above, Lu (2004) (on top) produced a construct with two single chain antibodies dimerized with each CH1-CL domain and with a constant CH2/CH3 region. The CH1-CL domain dimerizes two complete Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 12 antigen binding sites, each having a heavy and light chain. Zuo (2000) (middle) also produced an antibody with single chain antibodies (scFv p4G7; scFv p1C11) dimerized by each CH1-CL constant domain such the CH1-CL domain dimerizes complete antigen binding sites, each consisting of a heavy and light chain. In contrast, DVD-Ig uses the CH1-CL domain to pair the heavy and light chains of the antigen binding site (bottom). Abbott’s analysis is supported by this evidence because the only way CH1-CL is utilized in these two cited publications is to dimerize single chain antibodies (“scFv”). As illustrated by DVD-Ig, CH1-CL is utilized in a structurally different way in the claimed binding protein. Lu (2004) and Zuo (2000) would not have suggested to the skilled artisan a structure in which the CH1 is connected to a heavy chain and CL is connected to a light chain to pair the segregated light and heavy chains of an antigen binding site, as recited in the claims. In contrast, Drs. Davis and Verhoeyen testified that “[k]nowing that the ’830 approach works, it is not much of a leap for a skilled researcher to conceive of substituting the scFvs in Zuo 2000 and Lu 2004 (also known to work) with the ’830 VH-VH and VL-VL constructs and have a reasonable expectation that it will work.” Davis-Verhoeyen 1 Decl. ¶ 25. However, the expectation that a construct would work does not provide a reason as to why it would be made in the first place by one of ordinary skill. Müller Müller was also cited as providing a reason to utilize the CH1 and CL domains “to direct dimerization of polypeptides to which those domains are Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 13 fused.” Decision 9. However, as shown below, Müller utilizes the CH1-CL domain in the same way as in Lu (2004) and Zuo (2000). Müller, reproduced above, shows two single-chain antibodies (each with a heavy and light chain (“scFv”)) dimerized together by CH1 and CL domains, the same function they served in Lu (2004) and Zuo (2000). The domains do not pair the light and heavy chains as they do in the claimed binding protein. Summary While we concluded in the Decision that “[t]he evidence shows that the constant regions of an antibody and additional antigen binding domains were known to be useful in engineered proteins” (Dec. 26), upon further Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 14 consideration, in view of Dr. Kontermann’s testimony in paragraph 42 of his second Declaration, we conclude that the CH1-CL constant domains were not used in the cited prior art engineered antibodies (as they are in the claimed binding protein) to pair segregated heavy and light chains. Thus, we do not agree with Sanofi that the domains function in the same way in the claimed binding protein as in Müller, Lu (2004), and Zuo (2000). Sanofi 41.77c Comments 13. Sanofi’s statement is not supported by a preponderance of the evidence in the record presently before us. We also do not agree that predictability of the accessibility of domains and light and heavy chain assembly (id. at 13-15) are dispositive because there first must be a rationale to further modify the CH1-CL domain to segregate the CH1 and CL with the heavy and light chains of the double-head antibody to achieve the claimed structure. As reviewed above, Lu (2004), Zuo (2000), and Müller do not provided a reason to have utilized the CH1-CL domains as they are used in the claimed binding protein. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 15 Miller (2003) Miller (2003) attaches a constant region in a different way than Zuo (2000), Luo (2004), and Müller. Drawings from Miller (2003) are reproduced below. As shown in the figures reproduced above, Miller (2003) produced a construct in which the constant region (CH3/CH3-CH2/CH2) is attached to two CH1-CL regions, where each CH1-CL is attached to an antigen binding site to dimerize the light (VL) and heavy (VH) chains together. This structure is similar to how CH1-Cl is used in the claimed antibody (as illustrated in DVD-Ig above). There is one key different between Miller (2003) and DVD-Ig. These include: Miller (2003)’s construct comprises a CH1-CL region for each VL- Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 16 VH antigen binding site (1 and 2 in Miller (2003)’s figure reproduced above)2 while DVD-Ig has only one CH1-CL region associated with only one of the two VL-VH antigen binding sites. The question is whether there is an adequate reason, in view of Müller, Lu (2004), and Zuo (2000), to have adopted using Miller (2003)’s strategy when adding constant regions to the double-head antibody of the ’830 patent and whether, in doing so, the skilled artisan would have arrived at the claimed invention. In Sanofi’s Appeal Brief, it was argued that it would have been obvious to have eliminated the second CH1-CL region from Miller (2003): One of ordinary skill in the art would have been motivated to remove the outer CH1 and CL domains to reduce the size and complexity of the TA structure and more importantly because the '830 patent teaches that that two variable regions from the heavy or light chain can be linked in series via an amino acid linker (or directly connected without a linker) without affecting their binding function. Sanofi also contends that it would have been obvious to one of ordinary skill in the art, in view of the teachings of the '830 patent, to link the outer VL domain to the VL domain of the inner Fab fragment of the TA construct. One of ordinary skill in the art would have been motivated to link the outer and inner VL domain because the '830 patent teaches that two VL domains can be linked in series via an amino acid linker (or directly connected without a linker) without affecting their binding function, and because the skilled artisan would recognize that in the absence of the CH1 and CL domains of the outer Fab fragment, the outer VH and VL domains would be unlikely to properly associate. Sanofi Appeal Br. 20-21. 2 Accordingly, the structure of Miller (2003) has a CH1 linkage on the heavy chain between the two VH domains (i.e., the VD1 and VD2 domains recited in the claims), which is expressly excluded in claim 1 (i.e., “X1 is a linker with the proviso that it is not CH1”). Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 17 The Declarants in the Davis-Verhoeyen 2 Declaration further explained: Moreover, we contend that if Miller (2003) had removed the CH1 and CL domains from the TA construct’s outer Fab fragment, given the teachings in the '830 patent that tandem variable domains properly associate and yield two functional antigen binding sites despite lacking any adjacent constant domains, the authors would have been motivated to join the outer VL domain to the inner light chain Fab producing a light chain with tandem variable domains. Thus, it is our opinion that Miller (2003) shows that two binding sites (in the form of Fabs in this case) can be concatenated, and when linked to an Fc region, they result in a multivalent Ig-like molecule, having an “inner” binding site that is unaffected by the presence of an extra “outer” binding site. Davis-Verhoeyen 2 Decl. ¶ 27. Sanofi’s reasoning is not supported by a preponderance of the evidence. As discussed in Dr. Kontermann’s second Declaration, all the constructs described in Miller (2003) are Fab multimers in which identical Fab fragments are linked to each other. Kontermann 2 Decl. ¶ 24. A Fab fragment is the antigen binding portion of an Ig antibody comprising the VL, VH, CL, and CH1 domains. ’181 patent, col. 18, ll. 12-15; Miller (2003) 4856 (Fig. 1A). Dr. Kontermann testified that the Decision did not appreciate that Miller (2003) “teaches to multimerize a Fab fragment; the same Fab moiety is preserved throughout as an intact binding unit, and multimerization is achieved by connecting multiple Fabs through the heavy chains only.” Kontermann 2 Decl. ¶ 25. Dr. Kontermann’s testimony is consistent with the teachings in Miller (2003). Miller (2003) specifically discloses: Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 18 Based on the observation that cross-linking increases the efficacy of some mAbs [(citations omitted)], a set of three types of multivalent mAbs was designed: linear with tri- and tetravalent Fab repeats, a tetravalent F(ab’)2, and a tetravalent full-length IgG1. All three classes can be built from a basic linear Fab repeat. Any VH/CH1 domain of interest can be incorporated into the system through the use of unique restriction sites situated between the Fab repeats, i.e., separate PCR fragments of the VH/CH1 domain with the various restriction sites at the 5’ and 3’ ends allow for construction of two, three, four, or more tandem repeats of the VH-CH1. This can be expressed with a single L chain (VL-CL) to generate the multivalent Ab forms. Miller (2003) 4858 (“Discussion”). Thus, Miller (2003) describes the versatility of using a single repeated VH/CH1 domain to produce tandem antigen binding sites assembled with a single VL-CL chain. Because Miller (2003) teaches that its approach of using “a basic linear Fab repeat” (VH-CH1 and VL-CL) in tandem (Miller (2003), Abstract & 4858 (“Discussion”), eliminating a CH1 domain from one tandem domain but not the other tandem domain would be contrary to the express purpose of Miller (2003)’s “Fab repeat” strategy for constructing multimeric antibodies. The claimed binding protein, in contrast, uses VLA- VLB-CL to achieve an antibody with two antigen binding sites and using this one chain enables making an antibody with the same or different antigen binding sites. Sanofi states that the skilled worker would have eliminated the “outer CH1 and CL domains to reduce the size and complexity of the TA structure” of Miller (2003)’s construct, but did not point to scientific or declaration evidence to support this statement. Sanofi Appeal Br. 20. Sanofi also did not address the specific teachings in Miller (2003), as described by Dr. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 19 Kontermann, that “the same Fab moiety is preserved throughout as an intact binding unit, and multimerization is achieved by connecting multiple Fabs through the heavy chains only.” Kontermann 2 Decl. ¶ 25. Sanofi did not explain the obviousness of applying Miller (2003) in the context of the additionally cited Müller, Lu (2004), and Zuo (2000) publications which use the CH1-CL domains to dimerize single chain Fab fragments. Sanofi also argues that the ordinary skilled worker would have been motivated to link the outer and inner VL domain because the ’830 patent teaches that two VL domains can be linked in series via an amino acid linker (or directly connected without a linker) without affecting their binding function, and because the skilled artisan would recognize that in the absence of the CH1 and CL domains of the outer Fab fragment, the outer VH and VL domains would be unlikely to properly associate. Sanofi Appeal Br. 20-21. This argument is not persuasive. First, the fact that the VL domains can be linked in series and still retain activity is not a sufficient rationale to have done it. As discussed above, Miller (2003) describes specific reasons for utilizing a CH1 domain with each VH region, namely to achieve binding site multivalency with Fab repeats and a single VL-CL light chain. Second, Sanofi has not directed us to compelling evidence that “the outer VH and VL domains would be unlikely to properly associate” in the absence of CH1/CL and why this would have made it obvious, rather than non-obvious, to have eliminated the CH1/CL domain from the outer Fab fragment. OBVIOUSNESS IN VIEW OF NATURAL IgG Sanofi contends that the claimed binding protein is obvious because it “is essentially a natural IgG molecule that includes an extension of both Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 20 heavy and light chains to include an additional heavy chain variable domain on the heavy chain and an additional complementary light chain variable domain on the light chain.” Davis-Verhoeyen 2 Decl. ¶ 10. See also Sanofi Appeal Br. 10 (Jun. 6, 2012).3 We consider this argument in detail below. The person of ordinary skill in the art When making a patentability determination under 35 U.S.C., we consider the claims and the scope and content of the prior art to be directed to one of ordinary skill in the art. Thus, a determination as to whether the claims conform to the patentability requirements of 35 U.S.C., including the requirements of 35 U.S.C. § 103, is made from the perspective of one of ordinary skill in the art. In this case, the claimed subject matter involves an engineered binding protein which can be produced using molecular biology techniques (e.g., ’181 patent, col. 78). The binding protein utilizes immunoglobulin domains, including heavy and light chains and the Fc region. The cited prior art includes patents and peer-reviewed scientific journal publications. The latter is the forum for scientists who typically have Ph.D. or are working towards a Ph.D. or master’s degree in the pertinent field. Here, the pertinent fields are immunology and molecular biology, evidenced by the subject matter of cited prior art publications. Accordingly, 3 “Sanofi contends that it would have been obvious to one of ordinary skill in the art at the time the ’181 patent was filed, in view of the ’830 patent and Miller (2003), to add the constant region backbone of a natural IgG molecule (CH l-CH2-CH3/CL) to the tandemly arranged variable region molecules of the ’830 patent in order to accomplish the claimed invention of the ’181 patent.” Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 21 the prior art reflects that the person of ordinary skill in the art is a scientist, who publishes work in peer-reviewed scientific publications, has at least a post-graduate level understanding of immunology and molecular biology, and is able to perform engineering on proteins to produce a protein with desired binding activity. Natural IgG To support the statement that DVD-IgG is essentially a natural IgG with variable light and heavy chain extensions, Sanofi cited a book chapter by Dr. Kontermann in which he stated the DVD-Ig antibodies “‘look like normal IgG antibodies with the exception that a second VH and VL domain is fused N-terminal of the VH and VL domain of the heavy and light chain, respectively.’” Davis-Verhoeyen 2 Decl. ¶¶ 10, 25. Drs. Davis and Verhoeyen also testified: Moreover, by adding constant regions to an antibody fragment, disulphide covalent bridges that normally occur between the constant region domains would have formed as in a natural IgG molecule and, hence, disulphide covalent bridges were also not a novel feature of DVD-Ig molecules. Finally, when Dr. Kontermann discusses “non-covalent linkages that were, by design, not present in either the diabodies or the double heads of the ’830 Patent,” Second Kontermann Declaration ¶ 15, we believe that he must be referring to non-covalent interactions between the constant regions, which are an integral feature of constant regions in Ig molecules and therefore also not novel. Id. ¶ 11. Based on the knowledge of antibody structure, Drs. Davis and Verhoeyen further testified: Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 22 . . . an awareness of antibody structure and how this structure naturally facilitates correct assembly and concatenation of multiple domains, it is our opinion that the concept of adding a constant domain to tandem VL-VL domains and CH1-CH2-CH3 domains to tandem VH-VH domains does not require as great a leap of the imagination as AbbVie [Abbott] argues. Id. ¶ 20. Drs. Davis and Verhoeyen stated that because of the similarities to natural Ig and the teachings in the ’830 patent, it would have been predictable that interchain pairing would take place to produce a functional binding protein. Id. ¶¶ 29, 30. As indicated by Drs. Davis and Verhoeyen, there are strong similarities between the structure of DVD-Ig and a natural antibody. The drawings below show the structure of DVD-IgG (as illustrative of the claimed binding protein) and of a natural IgG (taken from Miller (2003)): The drawing on the left is of DVD-Ig; the drawing on the right is of natural IgG. As indicated in the second declaration of Davis and Verhoeyen, DVD-Ig differs from a natural IgG in having a second VH-VL antigen binding site (“Vb”) at the end of the antibody. Vb in DVD-Ig is not attached to the CH1-CL region normally associated with a variable antigen binding domain. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 23 In her Declaration, Dr. Reichert asserts that the skilled artisan “would not have manipulated the double heads in the ’830 Patent as proposed in the Decision, namely by adding structure to it ... because doing so would have been counterintuitive and against the very purpose for using antibody fragments.” Reichert Decl. ¶ 16. Dr. Reichert further stated “a person having ordinary skill in the art in August 2005 would have thought that they would be diminishing the supposed benefits of using fragments in the first place - their less complex nature and their ability to reach areas that the larger, full-length antibodies could not.” Id. Dr. Kontermann also expressed a similar opinion. Kontermann 2 Decl. ¶ 14. However, Drs. Davis and Verhoeyen responded in their second declaration: Dr. Reichert’s assertion is clearly undercut . . . by Alt et al., FEBS Letters 454: 90-94 (1999) (“Alt”) (Exhibit C), which lists Dr. Kontermann as the paper’s corresponding author, and which describes single-chain diabodies (scDbs) fused to constant domains. Specifically, the paper describes the benefits of engineered antibody fragments and then goes on to explain the reasons for adding extra structures to antibody fragments, stating that: In lacking the constant regions, recombinant antibody fragments also lack the associated effector functions and are rapidly cleared from serum due to their small size. However, certain therapeutic applications require an IgG molecule with its Fc- mediated effector functions and its long serum half- life. We sought to combine the advantages of single-chain diabodies with those of the IgG-Fc portion [by] creating IgG-like molecules. These molecules should possess the immune response- Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 24 mediating and pharmacokinetic properties of immunoglobulin molecules as well as four antigen binding sites. Alt, p. 90 (internal citations omitted). Davis-Verhoeyen 2 Decl. ¶ 15. Fig. 1 of Alt illustrates this concept: Alt’s Fig. 1 illustrates a single-chain bispecific construct on the far left, and then two such single-chain bispecific constructs linked by constant regions in the middle and on the right (CH2CH3 is Fc). The engineered antibody on the right has two bispecific antibodies and is therefore tetravalent (four binding sites) as is DVD-Ig. Thus, the second Davis-Verhoeyen declaration, with a specific citation to Alt, provides evidence of a reason to have utilized two bispecific variable regions linked together by constant regions to achieve Fc functionality in a tetravalent bispecific antibody. In the previous Decision, we had determined that it would have been obvious to have utilized the Fc region on the ’830 patent double- head antibody for the reasons set forth in the Request for Reexamination, that is, “to promote secondary immune function, lead to longer serum half-life, allow for simple purification by affinity chromatography, and permit efficient production in mammalian cells.” DOA 9 (quoting from Request for Reexamination 41). The Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 25 further evidence provided by Requester of adding an Fc region to an engineered bispecific antibody as described in Alt, co-authored by Patent Owner’s own declarant, provides strong evidence of the obviousness of utilizing Fc on a bispecific antibody fragment, such as the bispecific double-head antibody of the ’830 patent. CH-CL1 domain Sanofi provides several reasons as to why one of ordinary skill in the art would have further utilized the natural IgG CH1-CL domain when attaching the Fc region to the bispecific antibody of the ’830 patent. First, as indicated by Sanofi and illustrated by the drawings above, it is not new to utilize a CH1-CL domain in an antibody. The CH1-CL domain is part of the natural IgG antibody where it is located between the variable and Fc regions. Consequently, the skilled worker would have had reason to use it to produce an engineered antibody that mimicked the natural antibody as closely as possible. Consistently, Alt also expressly described producing “IgG-like antibodies.” Alt, p. 90. Second, Drs. Davis and Verhoeyen testified that the CH1-CL region would provide stability: 20. If a normally skilled antibody engineer (aware of the implications of the modular nature of antibodies) wanted to utilize all means to ensure that a bispecific or bivalent antibody construct was as stable as it could possibly be, then they would immediately think of adding the appropriate CH1 and CL domains. This would introduce an appropriately positioned disulphide bond between the two chains and add an extra set of non-covalent inter-chain association forces. Such a strategy would not be a creative leap, it would merely be following well- trodden paths of protein engineering and copying construction principles utilized naturally in the highly evolved vertebrate Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 26 immune system. There is no better way to enhance stable association between the two chains than to add constant domains. Davis-Verhoeyen 1 Decl. ¶ 20. Thus, the addition of the CH1-CL domain would add a disulfide bond and provide better stability to the construct in the same way it does for the natural IgG.4 Accordingly, one of ordinary skill in the art would have had reason to use CH1-CL domain in combination with the double-head antibody described in the ’830 patent for its expected benefit. In addition to these two reasons, Sanofi also stated that “the more pairing domains there are between two chains, the stronger the association will be between these two chains.” Davis-Verhoeyen 2 Decl. ¶ 22. Thus, providing a CH1-CL would be seen as increasing the strength of association between the chains, providing a rationale to use it in addition to the benefit of an additional disulfide bond. Sanofi further cited a statement in a review article published by Pluckthun (Andreas Pluckthun & Peter Pack, New protein engineering approaches to multivalent and bispecific antibody fragments, 3 Immunotechnology, 83-105 (1997)) of using a constant CL region to achieve dimerization: Beside these minimal motives based on helical structures, fusions to dimerizing enzymes and Ig domains as dimerization devices have also been investigated, but will not be discussed in detail. McGregor et al. have reported the use of whole k chain in 4 As indicated by Drs. Davis and Verhoeyen, the role of CH1 and CL in antibody assembly was well known at the time of the invention: “IgG assembly is stabilized by an interchain disulfide between CL, the LC [light chain] constant domain, and CH1, the first HC [heavy chain] constant domain.” Elkabetz et al., J. Biol. Chem. 280(15):14402-12, April. 15, 2005. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 27 a VH-linker-VL-CL molecule to achieve dimerization, while the CH3 domain has been fused directly to a scFv antibody or via a hinge region as discussed above. Pluckthun 93. As indicated by this statement, a constant region CL was used to achieve dimerization in an engineered antibody, namely by the non-covalent interactions between the natural CL domains. While the publication cited by Pluckthun did not utilize CL and CH1 domains, nonetheless, it demonstrated that the natural light chain constant region had an apparent benefit in promoting dimerization between antibody chains, supplying another reason to have mimicked the natural antibody by retaining the CH1-CL region when attaching the constant Fc region to the variable regions of the double- head antibody of the ’830 patent. While we had discussed the non-obviousness of utilizing the CH1-CL constant regions based on the teachings in Müller, Lu (2004), and Zuo (2000), in each of these cases, the regions were utilized to pair or dimerize protein chains together. See particularly, Zuo (2000) and Müller in which the CH1-CL domains pair single chain variable regions. This provides further evidence that the function of CH1-CL to stabilize protein chains and promote dimerization was known at the time of the claimed invention. Abbott’s principal argument against employing the CH1-CL region is lack of predictability of achieving the correct protein folding. For example, Dr. Kontermann stated: In the DVD-Ig format, the dynamics of association and dissociation of variable domains would be understood by a person skilled in the art to be incomparably different from the dynamics of an isolated double head fragment. For this reason, a person skilled in the art could not know whether both inner and Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 28 outer binding sites would properly form within the constraints of the novel DVD-Ig format, whether both binding sites could be functional, whether the outer binding sites would exhibit stability, or whether the inner binding sites constrained at both C-terminus and N-terminus would be both functional and accessible to antigen. Kontermann 2 Decl. ¶ 29. Dr. Kontermann also stated “it must also be considered that adding CH1 and CL constant domains adjacent selected variable domains would be expected to change the nature of interchain interactions and possibly hinder the ability of upstream domains to associate.” Id. at ¶ 30. Dr. Kontermann did not provide adequate evidence to support this opinion. As discussed by Sanofi, the prior art showed numerous engineered antibodies, having multiple binding sites and constant regions which were still capable of binding antigen. See, e.g., the drawings of Lu (2004), Zuo (2000), Müller, and Miller (2003) reproduced above. Indeed, these prior art antibodies utilized similar domains as in the claimed antibody in even more foreign ways to a natural IgG then they are used in DVD-Ig, yet assembly into at least some functional binding protein was observed. Thus, there is significant objective evidence before us of a plethora of engineered antibody structures, each which folded properly and was capable of some degree of antigen binding activity. Without a showing by Dr. Kontermann of substantial failure in the prior art, we do not have adequate evidence to credit his testimony over the conflicting testimony of Drs. David and Verhoeyen. For this reason, we do not find Dr. Kontermann’s testimony persuasive that, because the prior art engineered antibodies are different from DVD-Ig, they would not provide a Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 29 reasonable expectation of success that the structure of DVD-Ig would fold properly. Kontermann 2 Decl. ¶¶ 37, 38. Dr. Kontermann’s testimony that intrachain pairing is favored over interchain pairing is simply a reflection of the fact that the cited Müller (1998), Lu (2004), Lu (2005), and Zuo (2000) publications were utilizing single chain antibodies that required intrachain pairing to reconstitute the antigen binding site. Kontermann 2 Decl. ¶¶ 32, 33, 34, 44. However, in view of the fact the DVD-IgG utilizes a structure similar to the native IgG and interchain pairing was established to occur in the ’830 patent’s double- head antibody to produce functional antigen binding sites, we do not consider this argument persuasive as to the issue of unpredictability. Paragraph 35 of the second Kontermann declaration describes the production of non-functional dimers in Lu (2005). See also Kontermann 2 Decl. ¶ 55. However, Lu (2005) proposed a solution to this problem, and did not consider it a deterrent to making functional antibody.5 Drs. Davis and Verhoeyen responded that, nonetheless, fully functional engineered antibodies were obtained by Lu (2005). Davis-Verhoeyen 2 Decl. ¶ 31. Thus, while a specific combination of antibody chains in Lu (2005) may not have been functional according to Dr. Kontermann, functional antibodies assembled from the same chains did result. Lu (2005) thus is not evidence of a lack of expected success. 5 “Careful control of the balance of production of both the scFv-Fc fusion and the partnering cross-over scFv, for example via genetic manipulation of the expression vector, to favor the formation of the tetravalent molecule may reduce the secretion of the nonactive component.” Lu (2005) 19671. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 30 Dr. Kontermann asserted that the “addition of a new N-terminal domain would be expected to reduce flexibility of both chains, thereby calling into question whether the modified heavy and light chains would be capable of interacting as desired.” Kontermann 2 Decl. ¶ 19. However, the ’830 patent already teaches association of the heavy and light chains to form a functional bispecific double-head antibody. As concluded in the original Decision on Appeal, both double-head configurations described in the ’830 patent worked. Dec. 18-19. Thus, Dr. Kontermann’s argument about the lack of flexibility hindering interactions is not supported by the evidence in this record and inconsistent with the success described in the ’830 patent. The ’830 patent In the Decision on Appeal, we considered arguments about the unpredictability of the folding of the heavy and light chain segregants to make a tetravalent DVD-Ig. DOA 14-19. Dr. Kontermann provided additional testimony in his second declaration about the possibility of non- functional mispairing and multi-chain aggregates. Kontermann 2 Decl. ¶ 17. Dr. Kontermann also described examples in the ’830 patent in which he stated showed that changing the order of domains eliminated binding activity. Id. at ¶ 18. We have considered these arguments but, for the reasons already discussed in the previous Decision, are not persuaded by the evidence that there would not have been a reasonable expectation that a functional tetravalent antibody would be made. See DOA 14-19. For example, the cited prior art (Lu (2004), Zuo (2000), Miller (2003)) shows that even where there are multiple possible combinations between separate Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 31 chains and where only one combination results in the desired antibody, the desired antibody nonetheless forms in detectable and isolatable amounts. The disclosure cited by Dr. Kontermann in the ’830 patent that certain configurations would be less active or inactive (id. at ¶ 19-21) must be considered in light of the success reported in the ’830 patent of producing a bispecific antibody fragment with the same basic antigen binding structure as claimed, albeit without the CH1-CL and Fc regions. The disclosure in the ’830 patent that certain configurations are less active is not a teaching away because operable embodiments are described, including the one which serves as the basis of the rejection of the claim. Instead, such disclosure would be seen as guidance in how to make a functional bispecific antibody (e.g., switching domain order when a construct is inactive). Routine experimentation does not undermine obviousness. Drs. Davis and Verhoeyen provided further evidence of predictability, citing their own patent in which three functional antigen binding sites assembled to form a trivalent binding protein. Davis-Verhoeyen Decl. 2 ¶ 17-18. Dr. Kontermann cited EP 2 050 764 (EP ’764) as evidence that the double-heads of the ’830 patent were prone to incorrect pairing and aggregates. Kontermann 2 Decl. ¶ 20. However, EP ’764 was filed Oct. 15, 2007 and published Apr. 22, 2009, both dates which are after the filings dates of the ’181 patent (provisional applications filed Aug. 19, 2005 and Nov, 2, 2005; regular application filed Aug. 18, 2006). EP ’764 is therefore not prior art to the ’181 patent. It has not been established that the procedures followed in EP ’764 were indicative of the state of the art on the Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 32 filing date of the ’181 patent. Consequently, we have not given the statements in EP’764 significant weight. While we do not agree with Dr. Kontermann’s opinion that any unpredictability that DVD-Ig antibody could be made would have established a lack of a reasonable expectation of success, we acknowledge that the DVD-Ig was praised for its expression and stability, as discussed in detail below. Industry praise has been found to be probative evidence that one of ordinary skill in that art would not have expected success. Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino, 738 F.3d 1337, 1347 (2013). We address this praise, and other evidence of secondary considerations, in more detail below. SECONDARY CONSIDERATIONS To establish the non-obviousness of the claimed DVD-Ig, Abbott provided evidence of copying, industry praise, and long-felt need. While industry praise, copying, and long-felt need are probative evidence of the patentability of a claimed invention, “[t]o be afforded substantial weight, the objective indicia of non-obviousness must be tied to the novel elements of the claim at issue.” Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino, 738 F.3d 1337, 1346-47 (2013). In addition to this, there are numerous cases in which objective indicia of non-obviousness were insufficient to overcome a “strong” case of obviousness. For this reason, we are compelled to take a rigorous look at the invention through the lens of the prior art to determine whether the objective indicia of nonobviousness, which we acknowledge, are present here, are due to the merits of invention. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 33 Because the parts of an invention are almost always described in the prior art, and it’s their combination which constitutes the invention, the analysis must focus on whether the objective indicia of non-obviousness result from individual known parts functioning in their known way as expected or from the combination, itself. Copying Abbott asserted that Sanofi copied the claimed DVD-Ig. Specifically, Abbott provided evidence that Sanofi is developing a DVD-Ig binding protein as a new drug. Abbott’s Comments after Examiner’s Determination 19. However, Abbott acknowledged statements made by Sanofi that such binding protein was independently derived. Id. A declaration by Ercole Rao, Ph.D. (dated Nov. 24, 2011) was provided by Sanofi as evidence of this independent derivation. Abbott did not provide arguments or evidence to rebut Dr. Rao’s declaration. Not every competing product that arguably falls within the scope of a patent is evidence of copying. Otherwise every infringement suit would automatically confirm the nonobviousness of the patent. Rather, copying requires the replication of a specific product. This may be demonstrated either through internal documents . . . ; direct evidence such as disassembling a patented prototype, photographing its features, and using the photograph as a blueprint to build a virtually identical replica. Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1325 (Fed. Cir. 2004). As copying has not been established here, we do not find Abbott’s argument supported by sufficient evidence. Praise Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 34 We have focused on seven different publications provided by Abbott as evidence that its DVD-Ig antibody had been praised in scientific publications. See Appendix (“Praise”) excerpting pertinent passages from the publications. See also Patent Owner’s Response after Board Decision 11-13. Each of the publications, authored by scientists other than the inventors of the DVD-Ig technology, discussed the results obtained by the inventors as reported in a scientific publication of their work, Wu et al., Simultaneous targeting of multiple disease mediators by dual-variable- domain immunoglobulin, Nature Biotech., 25(11): 1290- 1297, Nov. 2007 (“Wu (2007)”). As discussed in the original Decision (DOA 22-23), in several of the publications, the authors specifically identified the segregation of the heavy and light variable domains into separate chains as part of the “solution” and “breakthrough” to problems encountered in bispecific antibodies. See Presta (2008), Fischer (2008), Morrison (2007), Beck (2010), and Michaelson (2009). However segregation of the heavy and light variable domains on separate chains (heavy chain segregant; light chain segregant) is described for the double-head antibodies of the ’830 Patent. The present invention provides a bispecific or bivalent antibody fragment analogue, which comprises a binding complex containing two polypeptide chains, one of which comprises two times a variable domain of a heavy chain (VH) in series and the other comprises two times a variable domain of a light chain (VL) in series. ’830 patent, col. 4, ll. 60-65 (emphasis added). Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 35 Presta (2008) also states the DVD-Ig solved the “light chain problem.” The so-called “light chain problem” described in Presta (2008) occurs when “one links two heavy chains (be they VH, VH-CH1, or full- length IgG) either chemically or by gene engineering, one is left with the difficulty of assuring that the two light chains partner with their correct heavy chains.” Presta (2008) 468. Presta (2008) stated that DVD-Ig solved this problem by fusing the variable light chain domains on a first chain and fusing the variable heavy domains on a second chain. Id. However, the fusion of light and heavy chain variable regions to produce light and heavy chain segregants had been described in the ’830 patent for a single bispecific antibody fragment. While the ’830 patent did not produce a tetravalent antibody with two bispecific binding fragments as claimed, Dr. Kontermann recognized that Miller (2003) “achieved a tetravalent binding protein but avoided the light chain problem by using the same VH-CH1 moiety and the same light chain (VL-CL) throughout.” Kontermann 2 Decl. ¶ 23. DVD-Ig uses the same heavy chain VHA-VHB and light chain VLA and VLB to make the tetravalent antibody, the same principle described in Miller (2003). Consequently, we do not find that Dr. Kontermann’s statement that “the teachings of the ’830 Patent and Miller (2003) are not relevant to each other” to be supported by the evidence in this record. Kontermann 2 Decl. ¶ 23. Several of the publications recognized that DVD-Ig had good yields and addressed poor expression encountered with other bispecific antibodies. See Presta (2008), Fischer (2008), Morrison (2007), Beck (2010), and Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 36 Gavrilyuk (2009). Gavrilyuk (2009) described DVD-Ig as a “promising breakthrough.” Gavrilyuk (2009) 3716-17. It is not evident from these publications or the record before us whether the praised stability/expression levels is a function of solving the light chain problem by following the principles in the ’830 patent and Miller (2003) and/or whether the addition of CH1-CL/Fc is also responsible for the praised results. However, as discussed above, CH1-CL was expected to improve assembly and stability. Dr. Reichert’s declaration was not helpful in showing that the praise was for a novel aspect of the invention. Dr. Reichert denied that the ’830 patent’s double-head antibody was “ground breaking” (Reichert Decl. ¶ 40) and opined that they were a “marginal” and “abandoned approach that failed to create a therapeutic antibody.” Id. at ¶ 39. However, we find Dr. Reichert’s declaration to lack credibility because, as discussed above, several of the publications cited by Abbott expressly describe the segregation of the variable regions into light and heavy chains as part of the elegant solution provided by DVD-Ig, and this aspect is specifically described in the ’830 patent. Dr. Reichert’s denial of the contribution of the ’830 patent technology is therefore inconsistent with the same publications cited by Abbott as praising DVD-Ig. Furthermore, as discussed above, the concept of using one type of heavy chain and one type of light claim to solve the “light chain” problem is described in Miller (2003). Yet, Dr. Reichert, who was fully aware of Miller (2003) (Reichert Decl., p. 2, indicating Miller (2003) was reviewed in preparing her declaration), opines (quoting from Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 37 Presta) that DVD-Ig “provides an ‘elegant solution’ to the long-felt light chain problem.” Id. at ¶ 27. Long-felt need In the previous Decision, we rejected arguments made by Patent Owner that the claimed DVD-IgG “solved a long-felt need for ‘the production of a bispecific, multivalent antibody-like construct, producible in sufficient quality and quantity, which would overcome recognized obstacles of complexity and lack of efficacy.’ (Patent Owner Resp’t Br. 12; Kontermann [1] Decl. ¶¶ 69-72).” DOA 24. Specifically, the Decision stated: By Dr. Kontermann’s own admission, another type of biospecific [sic, bispecific] antibody has been approved for therapeutic use (Kontermann Decl. ¶ 72). Thus, it cannot be said that others had failed in making biospecific [sic, bispecific] antibodies. Indeed, the prior art is replete with such examples, e.g., Lu 2005, . . , Müller, Zuo 2000, etc. Id. Dr. Kontermann in his second declaration responded: [T]he long-felt need in the art was not merely for a bispecific molecule, but for a bispecific molecule that was stable both in vitro and in vivo, easily expressed in mammalian cells, expressed in quantities enabling preclinical and clinical studies, easily purifiable, and which hopefully would solve some of the well-documented drawbacks of other structures of the prior art, e.g., the low efficacy, severe side effects, and immunogenicity mentioned by Muller and Kontermann in BioDrugs (2010), the ‘light chain problem’ mentioned by Dr. Presta in Presta (2008), and the aggregation problem mentioned by the Requester, sanofi, in EP 2 050 764 at ¶ 18. Many of these long-felt problems are solved at once by the DVD-Ig format. Kontermann 2 Decl. ¶ 53. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 38 As for the statement in the Decision that another bispecific antibody had been approved for use. Dr. Kontermann stated this antibody - catumaxomab - is a “quadroma generated by fusing mouse and rat hybridomas” which suffers from strong immunogenicity in human patients.” Id. Dr. Reichert further noted that catumaxomab was only approved for use in 2009 and has an inherent manufacturability problem in that it is the product of a quadroma (fusion of two different hybridomas), which leads to production of numerous non-functional isoforms.” Reichert Decl. ¶ 20. Dr. Reichert also stated that “it is clear that the DVD-Ig format provided a solution to at least two persistent and well-documented problems in the art relating to manufacturability and immunogenicity. Id. at ¶ 25. While catumaxomab was available as early as 1999 (Davis-Verhoeyen 2 Decl. ¶ 38), as discussed by both Drs. Kontermann and Reichert, the technology utilized to produce it had the major disadvantages of being made from non-human hybridomas resulting in strong immunogenicity when administered to humans and of problems with its manufacture. Even Drs. Davis and Verhoeyen acknowledged shortcomings in quadroma technology. Id. Thus, we agree that the problem of a bispecific antibody was not solved by catumaxomab. With respect to immunogenicity, however, there is no evidence that DVD-Ig solved that problem. Davis-Verhoeyen 2 Decl. ¶ 38. As testified by Drs. Davis and Verhoeyen, the use of human sequences was not new to DVD-Ig. Id. This testimony is supported by evidence in this record. For example: We have seen the development of increasingly sophisticated techniques to obtain human antibodies, ranging from Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 39 ‘humanizing’ . . . to the cloning and expression of genuine human antibody fragments . . . Clinical trials of several ‘humanized’ antibodies are in various stages of progress, and the results indicate that HAMA [human anti-mouse antibody] can indeed be overcome by this approach. Verhoeyen (1995) 1068. Dr. Reichert’s testimony that “it is clear that the DVD-Ig format provided a solution to” a “persistent and well-documented” problem relating to “immunogenicity” (Reichert Decl. ¶ 25) is inconsistent with the evidence in this record that the problem had indeed been solved by antibody humanizing technology, and casts doubt on the credibility of her declaration, particularly in view of her testimony that as “Editor-in-Chief of mAbs and President of the Antibody Society, I am uniquely qualified to provide an opinion on the state of the relevant art as of August 2005, long-felt needs in the field that the claimed DVD-Ig construct solved.” Id. at ¶ 9. In other words, such qualifications would mean that she was aware of antibody humanizing technology, but yet she did not explain how DVD-Ig had advanced a solution to the immunogenicity problem beyond what was provided by the prior art humanizing technology. We have not been directed to any features or limitations in claim 1 which address the so-called persistent immunogenicity problem. The Decision pointed to the prior art bispecific antibodies cited in the Decision as evidence that there were bispecific antibodies in the art, and therefore there was neither failure nor an “unmet” need for one. DOA 25. Dr. Kontermann addressed the Zuo (2000), Lu (2004), and Lu (2005) publications, citing evidence in Lu (2005) of difficulty in their production. However, as noted by Drs. Verhoeyen and Davis, although issues of Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 40 dimerization were noted, functional and high expression levels were reported by Luo (2005). Verhoeyen-Davis 2 Decl. ¶ 31. Abbott has not provided comparative data to determine whether the production levels observed with DVD-Ig were better than those in, for example, Luo (2005), or Alt (1999). Thus, we do not agree that Abbott established that the claimed invention met a long-felt need. Dr. Reichert stated that the original Decision misunderstood Morrison’s comments on the expression levels of DVD-Ig. Reichert Decl. ¶ 36. Dr. Reichert also appeared to believe that we had misunderstand that cited publications were praising DVD-Ig. Id. at ¶¶ 34-37. We clarify that at no time did we misunderstand that the praise in Morrison and the other cited publications was to anything other than DVD- Ig. Rather, the original Decision reached the conclusion based on the evidence that it was features already in the prior art which accounted for the successful expression of DVD-Ig. Dr. Reichert quoted from the Decision that the expression levels of DVD-Ig “’were facilitated by features that [were] . . . already known in the prior art to express well’” (id.), but did not identify a defect in this statement. Dr. Reichert merely explained that Morrison’s comments regarding expression levels represented a recognition that a complex immunoglobulin presents potential expression problems, but such problems were overcome by DVD-Ig. Id. We do not deny this. Instead, based on the evidence in this record, we conclude that the expression problems were overcome, or avoided, using structures known in the prior art to facilitate antibody expression, and that there were strong Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 41 reasons to have combined such prior art structures to have arrived at a binding protein with the scope of the claims. Claim scope We further note that the DVD-IgG used in Wu (2007) had specific linkers between the variable regions; Abbott has not demonstrated that its results with this construct is indicative of other constructs having different linkers (see claim 1, “X1 is a linker with the proviso that it is not CH1)”). Michaelson specifically referred the linker in DVD-Ig as allowing for stable assembly. See Praise: Appendix. However, such linker is not recited in claim 1. Discussion of secondary considerations Abbott has established that DVD-Ig was praised by the industry. However, as discussed above, the praise in part was of the light and heavy chain segregants, a feature described in the prior art ’830 patent. Also, the idea of using one type of chain to make a tetravalent antibody was described by Miller (2003). Thus, we do not find the praise with respect to this feature compelling evidence of non-obviousness. DVD-Ig also comprises constant domains CH1-CL and the Fc domain. Sanofi provided fact-based evidence of the obviousness of utilizing the CH1-CL domain in combination with the double-head antibody of the ’830 patent, namely: 1) added stability due to the presence of an additional disulfide bond (Davis-Verhoeyen 1 Decl. ¶ 20), 2) increased strength due to the association of CH1 and CL (Davis-Verhoeyen 2 Decl. ¶ 22); and 3) Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 42 dimerization domains to bring the variable heavy and light chains together assisting assembly of the antibody (Pluckthun, Müller, Lu (2004), and Zuo (2000). The CH1 and CL domains serve the same function they do in the native IgG in stabilizing the antibody with an interchain disulfide bond. Dr. Reichert referred to Presta’s reference to disulfide bond formation in DVD- Ig, but did not acknowledge that such bonds were also characteristic of a natural IgG. Reichert Decl. ¶ 33. Thus, even if the addition of the CH1-CL domains contributed to the praise, a preponderance of the evidence establishes that it was obvious to have included them and that the known and expected properties of these protein domains are responsible for the results. Thus, while we agree that stability and expression was praised, we have not been directed to evidence that it was anything more than the expected improvement from the obvious use of CH1-CL and Fc on the double-head antibody of the ’830 patent. We conclude that there is a strong showing of obviousness because the CH1 and CL domains, as well as the Fc region, were utilized in combination with the known double-head antibody of the ’830 patent for their known and expected properties. See e.g., Leapfrog Enters. Inc. v. Fisher-Price, Inc., 485 F.3d 1157, 1162 (Fed. Cir. 2007); Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1324 (Fed. Cir. 2004); Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d 1476, 1483-1484 (Fed. Cir. 1997) (Asyst Techs., Inc. v. Emtrak, Inc., 544 F.3d 1310, 1316 (Fed. Cir. 2008) (“[E]vidence of secondary considerations does not always overcome a strong prima facie showing of obviousness.”). Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 43 Abbott did not provide adequate evidence linking the praise to the merits of the invention beyond which was readily available in the prior art. See Ormco Corp. v. Align Technology Inc., 463 F.3d 1299, 1311-1312 (Fed. Cir. 2006) (in the context of commercial success). See also In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) where it was held that unexpected results could not be based on the property of a material known in the prior art for the same purpose. Specifically, DVD-Ig was praised for having light and heavy chain segregants, features of the ’830 Patent’s double-head antibody. For this reason, it cannot be said that despite the teaching in the prior art, the industry still praised the invention; rather, the praise was directed, at least in part, to a feature that already been described in the prior art, namely in the ’830 patent and Miller (2003). The benefit of the CH1 and CL domains in improving stability and antibody assembly was a well-known function of these domains. At the same time, we recognize that DVD-IgG comprising combination of heavy and light segregants and CH1-CL and Fc domains has been praised in numerous publications, providing strong evidence of the non-obviousness of the claimed DVD-Ig. See Pasteur, 738 F.3d at 1347. Abbott had the opportunity to establish that it was the unique combination that produced the praised features of stability and expression, and not the expected benefits of the Fc, CH1-CL, and heavy and light chain segregants. But they did not. In our opinion, because each one of these structures was utilized for its known and expected benefit, and there were strong reasons for assembling them together, the praise of the invention is not adequate to establish non-obviousness Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 44 In sum, we conclude, that despite the industry praise, it has not been established that the praise was due to the merits of the claimed invention, rather than of the known and expected advantages of utilizing heavy and light segregants joined to the constant regions of a natural IgG. It would have been obvious to one of ordinary skill in the art to have attached the Fc domain to gain its known effector function as described in Alt. The further use of the CH1-CL region would have been obvious based on its use in other engineered antibodies, its known stabilizing function in natural IgG, and the fact that it is configured in DVD-Ig in the same way it is exists in the natural IgG, i.e., adjacent to the Fc region. When the solution was so readily available in the prior art, and the person of skill in the art was a scientist highly skilled in protein engineering and immunology, in our opinion, the broad claims to a bispecific antibody, comprising heavy and light chain segregants arranged with constant regions as they are in nature is not warranted. SUMMARY For the reasons discussed above, the Examiner’s Decision in the Answer and Right of Appeal Notice not to adopt Rejections 2 and 3 is affirmed. However, based on new evidence and arguments, we find the claims obvious in view the ’830 patent and the evidence of Alt, Miller (2003), Müller, Lu (2005), Lu (2003), Lu (2004), and Zuo (2000). This 37 C.F.R. § 41.77(f) Decision is final. Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 45 TIME PERIOD FOR RESPONSE In accordance with 37 C.F.R. § 41.79(a)(1), the “[p]arties to the appeal may file a request for rehearing of the decision within one month of the date of: . . . [t]he original decision of the Board under § 41.77(a).” A request for rehearing must be in compliance with 37 C.F.R. § 41.79(b). Comments in opposition to the request and additional requests for rehearing must be in accordance with 37 C.F.R. § 41.79(c)-(d), respectively. Under 37 C.F.R. § 41.79(e), the times for requesting rehearing under paragraph (a) of this section, for requesting further rehearing under paragraph (d) of this section, and for submitting comments under paragraph (c) of this section may not be extended. An appeal to the United States Court of Appeals for the Federal Circuit under 35 U.S.C. §§ 141-44 and 315 and 37 C.F.R. § 1.983 for an inter partes reexamination proceeding “commenced” on or after November 2, 2002 may not be taken “until all parties’ rights to request rehearing have been exhausted, at which time the decision of the Board is final and appealable by any party to the appeal to the Board.” 37 C.F.R. § 41.81. See also Manual of Patent Examining Procedure § 2682 (9th ed., Rev. 07.2015, Nov. 2015). In the event neither party files a request for rehearing within the time provided in 37 C.F.R. § 41.79, and this decision becomes final and appealable under 37 C.F.R. § 41.81, a party seeking judicial review must timely serve notice on the Director of the United States Patent and Trademark Office. See 37 C.F.R. §§ 90.1 and 1.983. AFFIRMED; 37 C.F.R. § 41.77(f ) Appeal 2017-001183 Patent 7,612,181 B2 Reexamination Control 95/001,380 46 PATENT OWNER: YANKWICH & ASSOCIATES, P.C. 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