Ex Parte Carmeliet et alDownload PDFPatent Trial and Appeal BoardMar 24, 201713785559 (P.T.A.B. Mar. 24, 2017) Copy Citation 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. 13/785,559 03/05/2013 Peter CARMELIET BJS-5117-35 3858 23117 7590 03/28/2017 NIXON & VANDERHYE, PC 901 NORTH GLEBE ROAD, 11TH FLOOR ARLINGTON, VA 22203 EXAMINER GAMBEL, PHILLIP ART UNIT PAPER NUMBER 1644 NOTIFICATION DATE DELIVERY MODE 03/28/2017 ELECTRONIC 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. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): PTOMAIL@nixonvan.com pair_nixon @ firsttofile. com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte PETER CARMELIET, DESIRE COLLEN, SANDRO De FALCO, and RUVO MENOTTI1 Appeal 2016-000703 Application 13/785,559 Technology Center 1600 Before JEFFREY N. FREDMAN, JOHN G. NEW, and RYAN H. FLAX, Administrative Patent Judges. Opinion for the Board filed by New, Administrative Patent Judge. Opinion Concurring-in-Part, Dissenting-in-Part, filed by FREDMAN, Administrative Patent Judge. NEW, Administrative Patent Judge. 1 Appellants state the real parties-in-interest are Life Sciences Research Partners VZW and Vlaams Interuniversitair Instituut Voor Biotechnologie VZW. App. Br. 3. Appeal 2016-000703 Application 13/785,559 DECISION ON APPEAL Appellants file this appeal under 35 U.S.C. § 134(a) from the Examiner’s Non-Final Rejection of claims 1—17. Specifically, the claims stand rejected as unpatentable under 35 U.S.C. § 112, first paragraph, as lacking sufficient written descriptive support. Claims 1—17 also stand rejected as unpatentable under 35 U.S.C. § 112, first paragraph, as lacking enablement. Claims 1—17 stand further rejected under 35 U.S.C. § 102(b) as being anticipated by Boulton et al. (WO 99/24056, May 20, 1999) (“Boulton”). Claims 1—17 also stand rejected as unpatentable under 35 U.S.C. § 103(a) as being obvious over the combination of Boulton, M.J. Bottomley et al., Placenta growth factor (PIGF) induces vascular endothelial growth factor (VEGF) secretion from mononuclear cells and is co-expressed with VEGF in synovial fluid, 119 Clin. Exp. Immunol. 182-88 (2000) (“Bottomley”), Shitara et al. (US 6,986,890 Bl, January 17, 2006) (“Shitara”), Tchistiakova et al. (US 6,733,755 B2, May 11, 2004) (“Tchistiakova”), and Ferrara et al. (US 6,455,283 Bl, September 24, 2002) (“Ferrara”). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellants’ invention is directed to molecules that can inhibit the binding of PIGF to its receptor (VEGFR-1), such as monoclonal antibodies 2 Appeal 2016-000703 Application 13/785,559 and tetrameric peptides, and to the use of these molecules to treat pathological processes. Abstract. REPRESENTATIVE CLAIM Claim 1 is representative of the claims on appeal and recites: 1. A method of suppressing pathological angiogenesis or pathological arteriogenesis in an eye of a mammal, by administering to said mammal an antibody or fragment thereof that specifically binds to placental growth factor, that has no cross-reactivity to other proteins, and that neutralizes the activity of placental growth factor, thereby suppressing pathological angiogenesis or pathological arteriogenesis in said eye of said mammal, said antibody being a monoclonal antibody, a human antibody, a human monoclonal antibody, a humanized antibody, or a humanized monoclonal antibody; and said antibody fragment being a Fab, F(ab)'2 or scFv fragment. App. Br. 25. ISSUES AND ANALYSES We do not agree with the Examiner’s findings and conclusions that the appealed claims lack written descriptive support and are anticipated by, or obvious over, the combined cited prior art under 35 U.S.C. §§ 102(b) and 103(a). We agree with, and adopt, the Examiner’s findings and conclusion that the appealed claims lack enablement. We address the arguments raised by Appellants below. 3 Appeal 2016-000703 Application 13/785,559 A. Rejection of claims 1—17 under 35 U.S.C. $ 112, first paragraph for lack of written descriptive support Issue Appellants argue the Examiner erred because the language of the claims is supported by sufficient written descriptive support in Appellants’ Specification. App. Br. 13. Analysis The Examiner finds the limitation of claim 1 reciting “an antibody or fragment thereof... that has no cross-reactivity to other proteins” does not receive adequate written descriptive support in Appellants’ Specification. Non-Final Act. 3. The Examiner finds the only reference to this limitation is in paragraph [0018] of the Specification, which recites: The terms “antibody” or “antibodies” relate to an antibody characterized as being specifically directed against P1GF or VEGFR-1 or any functional derivative thereof, with the antibodies being preferably monoclonal antibodies, or an antigen-binding fragment thereof, of the F(ab')2, F(ab) or single chain Fv type, or any type of recombinant antibody derived thereof. These antibodies of the invention, including specific polyclonal antisera prepared against PIGF or VEGFR-1 or any functional derivative thereof have no cross-reactivity to other proteins. The monoclonal antibodies of the invention can, for instance, be produced by any hybridoma liable to be formed according to classical methods from splenic cells of an animal, particularly of a mouse or rat immunized against PIGF or VEGFR- 1 or any functional derivative thereof, and of cells of a myeloma cell line, and to be selected by the ability of the hybridoma to produce the monoclonal antibodies recognizing PIGF or VEGFR-1 or any functional derivative thereof that have been initially used for the immunization of the animals. 4 Appeal 2016-000703 Application 13/785,559 (emphasis added). The Examiner thus finds Appellants’ Specification does not: provide sufficient written description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of a species or a genus of anti-placental growth factor antibodies having the binding, inhibiting and treating functions and including no cross reactivity to other proteins, broadly encompassed by the claimed invention. Non-Final Act. 3 (emphasis added). The Examiner finds further that the recitation of no cross-reactivity to other proteins, by the plain language of the Specification, is interpreted to mean “no cross-reactivity to any other protein.” Non-Final Act. 4. The Examiner points to several prior art references that teach that antibodies, including anti-human P1GF antibodies, can routinely be expected to have a degree of cross-reactivity with other proteins.2 Id. at 4—5. The Examiner therefore finds that Appellants’ Specification fails to provide a disclosure of an anti-PIGF antibody having the claimed functional characteristics of 2 The Examiner cites, e.g., G. Kijanka et al., Rapid Characterization of Binding Specificity and Cross-Reactivity of Antibodies Using Recombinant Human Protein Arrays, 340(2) J. Immunol. Methods 132—37 (2009); J.A. Berzovsky and I.J. Berkower, Antibody-Antigen Interactions and Monoclonal Antibodies, in Antigen-Antibody Interactions and Monoclonal Antibodies in Fundamental Immunology, Sixth Edition, 152—91 (W. Paul, ed., 2008); J.E. Park et al., Placenta Growth Factor. Potentiation of Vascular Endothelial Growth Factor Bioactivity, in vitro and in vivo, and High Affinity Binding to Flt-1 but not to Flk-l/KDR, 269(41) J. Biol. Chem. 25646—54 (1994); ThermoFisher Product Data Sheet for PLGF Antibody. 5 Appeal 2016-000703 Application 13/785,559 binding, inhibiting and treating and that has no cross-reactivity to any other protein, as claimed. Id. at 6. The Examiner concludes that an artisan of ordinary skill would not be able to visualize or recognize the identity of the members of the genus that exhibit this functional property. Id. Appellants argue that their Specification discloses antibodies and antibody fragments. App. Br. 13 (citing Spec. H 8, 13, 14, 16, 18). Appellants argue that the Specification further discloses murine monoclonal antibody MabPL5Dl 1 against P1GF; production of monoclonal antibodies against murine PIGF-2; and subcloning of the five positive clones with subsequent production of monoclonal antibodies that were again tested for inhibition of binding of m-PIGF-2 to Flt-1/Fc. App. Br. 14—15 (citing Spec. 1175—80). Appellants therefore argue that a person of ordinary skill would understand from the whole of the Specification that Appellants were in possession of the claimed invention at the time the application was filed. App. Br. 15. We do not agree with the Examiner’s findings. “[T]he test for sufficiency is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.” Ariad Pharms., Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010). Appellants’ Specification discloses: “These antibodies of the invention, including specific polyclonal antisera prepared against P1GF or VEGFR-1 or any functional derivative thereof, have no cross-reactivity to other proteins.” Spec. 118. Although we find Appellants’ Specification presents a de minimis written description, we find it just sufficient to reasonably convey to a person of ordinary skill in the art of immunology an understanding that 6 Appeal 2016-000703 Application 13/785,559 Appellants’ had possession of “an antibody or fragment thereof... that has no cross-reactivity to other proteins,” as recited in the claims. We consequently reverse the Examiner’s rejection on this ground. B. Rejection of claims 1—17 under 35 U.S.C. $ 112, first paragraph for lack of enablement The Examiner repeats his findings in support of his conclusion that Appellants’ claims on appeal are not enabled. Non-Final Act. 6—11. Again, Appellants do not directly address the Examiner’s conclusion that Appellants’ Specification does not enable the limitation of claim 1 reciting “an antibody or fragment thereof... that has no cross-reactivity to other proteins.” We find the Examiner has the better position on this issue. Section 112 requires that the patent specification enable “those skilled in the art to make and use the full scope of the claimed invention without ‘undue experimentation’” in order to extract meaningful disclosure of the invention and, by this disclosure, advance the technical arts. Invitrogen Corp. v. Clontech Labs. Inc., 429 F.3d 1052, 1070-71 (Fed. Cir. 2005). Furthermore, the specification must teach those of skill in the art “how to make and how to use the invention as broadly as it is claimed.” In re Goodman, 11 F.3d 1046, 1050 (Fed. Cir. 1993). We agree with the Examiner that Appellants’ Specification lacks a sufficient disclosure to enable a person of ordinary skill to make and use the full scope of an antibody or fragment thereof that has no cross-reactivity to any other proteins, as required by the claims. This is particularly so in view of the prior art with respect to the well-known cross-reactivity of 7 Appeal 2016-000703 Application 13/785,559 monoclonal antibodies in the art, as cited by the Examiner in the findings concerning Appellants’ written description arguments, discussed supra. We consequently affirm the Examiner’s rejection of the claims. C. Rejection of claims 1—17 as anticipated and/or obvious Issue Appellants argue the Examiner erred in finding Boulton discloses the limitation of claim 1 reciting “an antibody which is a monoclonal antibody, a human antibody, a human monoclonal antibody, a humanized antibody, or a humanized monoclonal antibody or an antibody fragment that is a Fab, F(ab)'2 or scFv fragment.” App. Br. 18. Analysis Appellants argue the Examiner has ignored the claims, as amended, to include the disputed limitation, and contend that Boulton fails to disclose each and every aspect of the claimed invention. App. Br. 18. Furthermore, Appellants argue Boulton fails to establish a causative relationship between P1GF and proliferative diabetic retinopathy (PDR). Id. at 19. Appellants contend that it would not have been clear to a person of ordinary skill in the art whether P1GF is a resultant consequence of PDR or one of the many possible causes of PDR. Id. According to Appellants, in the absence of such causal relationship, there would have been no expectation of success in treating PDR by blocking P1GF. Id. Appellants also point to Boulton’s disclosures: (1) “that inhibitors of P1GF ... are able to reduce, prevent or regress ocular angiogenesis”; and (2) that “P1GF and functional derivatives or fragment thereof may also be used 8 Appeal 2016-000703 Application 13/785,559 to prevent ocular revascularization in conditions such as the PDRs.” App. Br. 19 (citing Boulton 3—4). Appellants therefore contend Boulton discloses contradictory teachings with respect to whether P1GF activity should be decreased or increased in order to prevent ocular angiogenesis, which, Appellants contend, would have confused a person of ordinary skill in the art as to whether there existed any reasonable expectation of therapeutic success in modulating (positive or negative) P1GF in the treatment of any eye disorder. Id. The Examiner responds that Boulton explicitly discloses inhibitors of P1GF in treating pathological conditions encompassed by the claimed methods and described in Appellants’ Specification, including “angiogenesis, proliferative diabetic retinopathies for the reduction, prevention or regression of subretinal neovascularization, iris neovascularization resulting in glaucoma, rubeosis, comeal/retinal vascularization.” Ans. 9 (citing Boulton 3, 4, Examples 1, 2). The Examiner finds Boulton also discloses using anti-PIGF antibodies as inhibitors of P1GF. Id. (citing Boulton 3—10, claim 10). With respect to Appellants’ arguments that the disclosures of Boulton are contradictory, the Examiner finds Boulton discloses P1GF or functional derivatives I fragments may be used to stimulate or inhibit angiogenesis depending upon the specific condition to be treated. Ans. 10 (citing Boulton 4). The Examiner finds no contradiction in neutralizing antibodies against P1GF as inhibitors of various pathological conditions, including regulation of ocular angiogenesis and the proliferative diabetic retinopathies recited by Appellants’ claims on appeal. Id. 9 Appeal 2016-000703 Application 13/785,559 We are not persuaded by the Examiner’s findings and conclusions. As we have explained supra, with respect to Appellants’ enablement arguments, we are not persuaded that Appellants have provided an enabling disclosure of the limitation reciting “an antibody ... that has no cross reactivity to other proteins.” However, in the Non-Final Rejection, the Examiner does not cite to any of the prior art references as disclosing this particular limitation, nor can we find any disclosures in the prior art that teach or suggest such a limitation. Indeed, the Examiner does not identity a teaching in Boulton for a monoclonal antibody with narrow specificity and high affinity limited to the P1GF target. Because the Examiner does not adduce any evidence disclosing this limitation of the claims on appeal, we reverse the Examiner’s rejection on this ground. Furthermore, and for the same reasons, we reverse the Examiner’s rejection of the claims as being obvious under 35 U.S.C. § 103(a). DECISION The Examiner’s rejection of claims 1—17 as unpatentable under 35 U.S.C. § 112, first paragraph, for lack of written description is reversed. The Examiner’s rejection of claims 1—17 as unpatentable under 35 U.S.C. § 112, first paragraph, for lack of enablement is affirmed. The Examiner’s rejection of claims 1—17 as unpatentable under 35 U.S.C. § 102(b) is reversed. The Examiner’s rejection of claims 1—17 as unpatentable under 35 U.S.C. § 103(a) is reversed. 10 Appeal 2016-000703 Application 13/785,559 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1). See 37 C.F.R. § 1.136(a)(l)(iv). AFFIRMED CONCURRING-IN-PART, DISSENTING-IN-PART OPINION FREDMAN, Administrative Patent Judge. I fully concur with the opinion of the Majority regarding affirmance of the enablement rejection and reversal of the anticipation and obviousness rejections. I respectfully dissent from the Majority’s result reversing the written description rejection. In my opinion, the Examiner’s rejection is consistent with the reasoning of Centocor Ortho Biotech, Inc. v. Abbott Laboratories, 636 F.3d 1341, 1351 (Fed. Cir. 2011) and AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014). Principles of Law “[T]he asserted claims constitute a wish list of properties that a fully human, therapeutic TNF-[a] antibody should have: high affinity, neutralizing activity, and the ability to bind in the same place as the mouse 11 Appeal 2016-000703 Application 13/785,559 A2 antibody.” Centocor, 636 F.3d at 1351. “The specification at best describes a plan for making fully-human antibodies and then identifying those that satisfy the claim limitations. But a ‘mere wish or plan’ for obtaining the claimed invention is not sufficient.” Id. While our precedent suggests that written description for certain antibody claims can be satisfied by disclosing a well- characterized antigen, that reasoning applies to disclosure of newly characterized antigens where creation of the claimed antibodies is routine. . . . Claiming antibodies with specific properties ... can result in a claim that does not meet written description even if the [target] protein is disclosed because antibodies with those properties have not been adequately described. Id. at 1352. Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie, 759 F.3d at 1301. “The asserted claims attempt to claim every fully human 1L—12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara, whereas the patents do not describe representative examples to support the full scope of the claims.” Id. Findings of Fact 1. The Specification teaches “a murine monoclonal antibody against P1GF. In another specific embodiment, the murine monoclonal antibody is MabPL5Dl 1” (Spec. 117). 12 Appeal 2016-000703 Application 13/785,559 2. The Specification teaches the “antibodies of the invention, including specific polyclonal antisera prepared against P1GF or VEGFR-1 or any functional derivative thereof, have no cross-reactivity to other proteins” (Spec. 118). 3. The Specification teaches “antibodies or functional fragments thereof can be used for the manufacture of a medicament for the treatment of the above-mentioned disorders” (Spec. |44), with the list of disorders comprising “ischemic retinopathy, tumor formation, pulmonary hypertension, edema and inflammation” (Spec. 112). 4. The Specification teaches: “Anti-PIGF antibodies, which blocked the PIGF response of endothelial cells . . . reduced vascular leakage in wild-type mice application of mustard oil on their ears” (Spec. 179). 5. The Specification teaches “120 hybridomas were produced, of which showed a 50% inhibition, 38 showed 70% inhibition and five gave complete inhibition of binding of rmPIGP-2 to its receptor (Fit-1)” (Spec. | 75). 6. Table 3 of the Specification is reproduced below: Molar excess versus rn-HGF-2 Nr to X sx 2.5 X 1.25 X No antibody 1 MJH5G5 66 64 63 89 100 £ PL5DI1D4 10 15 22 43 100 PL5D11F10 14 10 22 35 100 3 PL13FUC8 57 70 S3 100 100 4 PL17AI0EI2 40 46 60 m 100 PL17A1GF12 41 41 53 90 100 Negative control Irrelevant antibody l C 8 100 100 100 100 100 Concentration of rn-PJGP-2 in rig/’ml 5 5 5 5 5 Concentration of antibody in ng/ml 200 100 50 25 0 13 Appeal 2016-000703 Application 13/785,559 “Table 3: Inhibition by anti-murine P1GF-2 Mab of murine PIGF-2 binding to murine Flt-1/Fc. The data represent residual m-PlGF-2 in percent” (Spec. 177). Analysis In my view, the central issue in this written description requirement is the functional requirement in claim 1 that the antibody, in addition to specifically binding P1GF, also “has no cross-reactivity to other proteins” and functions to neutralize P1GF thereby “treating pathological angiogenesis or arteriogenesis.” I do not dispute that two particular antibodies that inhibit P1GF are described (FF 1, 4). However, I conclude that the functional requirements that this peptide also have no cross-reactivity with other proteins and the functional requirement that the antibodies neutralize P1GF and treat pathological angiogenesis and arteriogenesis are the sort of wish list of properties which fails to satisfy the written description requirement since claiming “antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described.” Centocor, 636 F.3d at 1352. While the Specification claims that of 120 hybridomas, 15 showed 50% inhibition, 38 showed 70% inhibition and five gave complete inhibition (FF 5), the data in Table 3 belies that disclosure, showing no complete inhibition for any of the tested antibodies where several of the monoclonal antibodies substantially failed to inhibit binding at 1.25 fold molar excess, 14 Appeal 2016-000703 Application 13/785,559 and PL1H5G5 and PL13F11C8 retained more than 50% activity even at 10 fold molar excess (FF 6). Moreover, the issue is not binding to P1GF but rather the absence of description in the Specification of a routine method for obtaining antibodies with the other functional properties of claim 1. In particular, the Specification is entirely silent on disclosing a single antibody that has no cross-reactivity with other proteins. There is no disclosure in the Specification of what antibody structures, antigens, or other information is necessary to obtain the functional result of avoiding cross-reactivity while retaining neutralizing activity and treating the specific pathological conditions. Consequently, the instant “claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad’s claims, cover any compound later actually invented and determined to fall within the claim’s functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010). In Abbvie, an antibody with a particular binding rate was found to lack descriptive support for the entire genus even though over 200 antibodies were disclosed because “[although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.” Abbvie, 759 F.3d at 1300. Here, only one antibody was deposited (FF 1) and two total disclosed with part of the functionality required by claim 1 (FF 4), with no antibody demonstrated to have no cross reactivity with other proteins. Thus, while there is not a bright line rule for the number of species necessary to support a 15 Appeal 2016-000703 Application 13/785,559 generic claim, I would find the current Specification insufficient because the “claims attempt to claim every . . . antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity . . . whereas the patents do not describe representative examples to support the full scope of the claims.” Id. at 1301. Appellants contend the “level of skill in the art of making antibodies that specifically bind to a desired protein, or that are specifically directed to a desired protein, or that do not cross-react to other proteins, or that neutralize the activity of a desired protein are well known in the art” (App. Br. 9). In Ariad, where a single specific inhibitor, IeB, was taught by the Specification, Ariad found that “a vague functional description and an invitation for further research does not constitute written disclosure of a specific inhibitor insufficient to satisfy the written description requirement. Ariad, 598 F.3d at 1356. Similarly, in the instant case, the possession of a very limited number of species of antibody that may themselves lack the cross-reactivity requirement and without any structure or reliable methodology to produce other antibodies which necessarily have the functional properties of “not cross-reacting to other proteins” and “treating pathological angiogenesis or arteriogenesis” lacks written description. This is precisely the sort of situation where Appellants have expressed a wish. A wish for an antibody with certain functional properties. It is a fine, useful, and desirable wish, but a wish nonetheless. There is no description of the antigen or process necessary to obtain this antibody. There are, at best, two examples of such an antibody with no structural description of the antibody itself. There is no description in the 16 Appeal 2016-000703 Application 13/785,559 Specification of any method which could be reliably used to obtain this antibody. Centocor mandates that a ‘“mere wish or plan’ for obtaining the claimed invention is not sufficient.” Centocor, 636 F.3d at 1351. Here, Appellants’ Specification lacks even a plan, retaining only the wish. For these reasons, I dissent from the Decision of the Majority and would affirm the Examiner’s written description rejection. 17 Copy with citationCopy as parenthetical citation