Ex Parte 7612181 et al

Patent Trials and Appeals Board

Mar 21, 2014

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

UNITED STATES PATENT AND TRADEMARKOFFICE 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 04/05/2017 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 04/05/2017 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) Appeal 2017-01183 Patent 7,612,181 Reexamination Control 95/001,380 Appendix: PRAISE The following passages are excerpted from the publications cited by Patent Owner in praise of DVD-Ig as described in the post-filing date publication by the inventors. Wu (2007). The passages relating to segregation of heavy and light chains is in bold; underlined portions relate more to expression. 1. Presta (2008) Bispecific antibodies have been a subject of research and therapeutic mAb development for many years, engendering an astonishing array of antibody formats for achieving the linking of two (or more) antigen binding domains. Many of these engineered antibody formats have been devised to counter an innate problem in bispecific antibodies-what has been referred to as the 'light chain' problem. If one links two heavy chains (be they VH, VHCH1, 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; if they do not, then the binding affinity/specificity of the resulting mismatched VLNH pairs in the bispecific moiety are compromised. Though theoretically one might solve this by using two Fabs that can share the same light chain without compromising function, the majority of bispecific formats have utilized variations of the scFv format, that is physically linking the VL and VH domains so that (hopefully) each VL will pair only with its proper VH, as at least one of the VLNH pairs in the bispecific antibody. 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-CHl) [63] A number of 'dual variable domain antibodies' (DVD-Ig) were constructed and analysis of binding showed that these constructs could indeed bind to the two intended targets and retain affinity similar to the parental mAbs, though retention of affinity can be influenced by variable domain position (i.e. VL1-VL2 versus VL2- VLl) or be compromised regardless of variable domain position. Regardless of these limitations, the DVD-Ig expressed well, folded Appeal 2017-01183 Patent 7,612,181 Reexamination Control 95/001,380 correctly (including disulfide bond formation), and exhibited pharmacokinetics similar to the parental mAbs. Page 468 2. Fischer (2008) To maintain Fc-mediated functions as well as a longer serum half-life, several IgG-like bispecific formats have been developed. In most cases these molecules have turned out to be a challenge to manufacture and are relatively unstable in vivo [reference, inter alia, to Lu (2004)]. However, a breakthrough in this area has been achieved recently by fusing two VL and two VH domains in tandem at the extremities of the IgG constant regions. This so- called dual-variable-domain immunoglobulin (DVD-lg; Figure ID) may be generally applicable as several pairs of specificities could be successfully combined into this format [reference to Wu (2007)]. Importantly, the production yield, in vivo stability and pharmacokinetic properties of a DVD-Ig neutralizing IL-la and IL-1 were found to be very similar to conventional monoclonal antibodies. Furthermore, the in vivo efficacy of this molecule in an animal model of rheumatoid arthritis was similar to co-administration of two monoclonal antibodies directed against the same cytokines, rendering this particular class of molecules very promising, Page 835. 3. Morrison (2007) Recombinant DNA technology has also been used to produce bispecific antibody fragments of many different forms (Fig. 1c-f), including diabodies, in which two scFvs (Fig. 1e) of differing specificities are linked4 (Fig. Id) [shows L and H segregated] . . . . These have the advantage that they can be expressed at high levels in bacteria, and their small size enhances their penetration into tumors. They also clear rapidly; this can be advantageous for some applications but is a problem if persisting high levels of the therapeutic are required. A major limitation of all these antibody fragments Appeal 2017-01183 Patent 7,612,181 Reexamination Control 95/001,380 is that they lack the constant region of the antibody with its associated functional properties. Page 1233. Wu et al. describe a new approach for producing complete antibody molecules with two different binding specificities, which they name dual-variable domain immunoglobulin or DVD-Ig (Fig. 1g). Each light and heavy chain contains two different variable regions joined by short linker sequences. . . . For this protein [DVD-Igs], they were able to establish Chinese hamster ovary cell lines that produced it at levels comparable to those seen for a conventional human IgGl. Thus the problems of poor expression frequently encountered with complex molecules such as bispecific antibodies were not seen with proteins of this structure, making it feasible to pursue more extensive preclinical and clinical testing. Page 1233-34. The report by Wu et al. provides convincing evidence that it will now be possible to produce bispecific antibodies that can simultaneously bind and neutralize two soluble proteins. Page 1234. 4. Beck (2010) Bispecific antibodies directed against two different tumour associated or immunological antigen targets are another strategy that has been investigated, but with only limited success owing partly to the highly heterogeneous mixtures that result from the multiple possibilities of immunoglobulin chain association and also to scale-up and purification issues . . . Page 348. These difficulties have been recently overcome by the dual variable domain IgG (DVD-IgG) technology. This new type of immunoglobulin was obtained by combining the variable domains of two already characterized monoclonal antibodies (two V1 Appeal 2017-01183 Patent 7,612,181 Reexamination Control 95/001,380 domains on the light chain and two VH domains on the heavy chain) . . . This technology enables the different specificities of two monoclonal antibodies to be engineered into a single functional, dual- specific, tetravalent IgG like molecule, and these antibodies can be made with good production yields in a scalable Chinese hamster ovary (CHO) cell line. Id. 5. Craig (2012) In the studies described here, we seek to design DVD-Igs that can most effectively deliver cytotoxic ICs to cells expressing HIV Env on their cell surface. . . We have chosen to make DVD-Igs, rather than a bifunctional Ab as did Mouquet, et al, because the DVD-Igs are potentially tetravalent. . . While others have sought Abs with greater HIV-neutralizing activity, the goal of our studies is to produce better anti-HIV ICs. Here we systematically examine the role of linker length, linker type, and domain orientation on binding and effector functions of the DVD-Igs. The results show that the design of the V- domains can determine which biological functions will predominate. Results show the DVD-Igs always outperform the less effective parental Ab and generally equal the activity of the better one, in some cases exceeding the function of the better. Page e46778. 6. Michaelson (2009) More recently, a report by Wu and colleagues described a promising technology for producing dual-targeting N-terminal Ig-like BsAbs referred to as dual-variable domain (DVD) IgGs that were shown to exhibit favorable PK [pharmokinetic] properties and in vivo activity comparable to that of the combined mAbs. The DVD technology links the VL and VH domains (Fv) specific to one target in series to the corresponding domains of an IgG specific to a second target using the naturally occurring conserved “elbow” sequences located at the amino terminus of CL and CH1. It was proposed that Appeal 2017-01183 Patent 7,612,181 Reexamination Control 95/001,380 the flexibility of the elbow sequences and absence of strong secondary structure allows for stable assembly of the added N-terminal Fvs. Page 136 (the claims of the ’181 patent are not limited to a specific linker which links the variable domains together). 7. Gavrilyuk (2009) Despite numerous attempts over the past two decades to develop viable approaches to synthesis of bi and multi-specific antibodies, no such antibodies are approved drugs. Protein engineering approaches for the creation of bispecific antibodies have been challenging due to issues of protein stability and difficulties in obtaining high-level expression. Indeed, only recently have promising breakthroughs been reported. (Citing Wu (2007.) Page 3716-17. Appeal 2017-01183 Patent 7,612,181 Reexamination Control 95/001,380 PATENT OWNER: Yankwich & Associates, P.C. (And Abbott Bioresearch Center) 201 Broadway Cambridge, MA 02139 THIRD PARTY REQUESTER: McDonnell, Boehnen, Hulbert & Berghoff, LLP 300 S. Wacker Drive 32nd Floor Chicago, IL 60606