DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application claims benefit under 35 U.S.C. 119(e) to U.S. Provisional applications 61/815219, filed 4/23/2013, 61/659,752, filed 6/14/2012, and 61/595216, filed 2/6/2012.
Status of Claims
Claims 1-20 are pending and are being examined on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by 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 the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the claimed genus
Independent claim 1 recites a method of using a genus of antibodies that are humanized monoclonal antibodies that bind to a particular discontinuous epitope on human CD47 that is a loop comprising SEQ ID NO: 56 and amino acid residues Y37, T102, and E104 numbered in accordance with SEQ ID NO: 147. The antibodies of claim 1 possess three functions: (1) binding human CD47 at the defined epitope; (2) a negative function of not causing a significant level of agglutination of red blood cells; and (3) the ability to treat a hematological cancer.
Dependent claims 2-4 recite additional functional properties. Dependent claim 5 further defines the discontinuous epitope that is bound by the antibody. Dependent claims 6-13 recite that the antibodies comprise particular Fc regions. Defining the Fc region of the antibody provides additional structure, but an Fc region does not mediate binding to the epitope.
Dependent claims 14 and 15 recite additional limitations regarding the orientation and positioning of the antibody when bound to the epitope. Dependent claims 16-20 recite additional limitations with respect to the method of treating. None of the claims define the structure of the antibody binding domain beyond the general description that it is a “humanized monoclonal antibody”. All of the claims recite a genus of anti-CD47 monoclonal antibodies that are defined almost entirely in terms of function, and many of the claims require multiple functions; therefore the claims encompass a genus of anti-CD47 antibodies with unidentified binding domains including, and extending beyond, those embodiments described in the specifications.
State of the Relevant Art
The invention relates to antibodies that bind human CD47. CD47 has been fully described by amino acid sequence in human, mouse, rat, and a number of other species. E.g., Subramanian et al., J Biol Chem 2007; 282:1805-18 (IDS). It is also known as integrin-associated protein (“IAP"). Id. CD47 mediates cell-cell interactions via the counterreceptor “signal regulatory protein alpha” (“SIRPα”). Antibodies to CD47, including mouse antibodies to human CD47 that block SIRPα, were known in the art. E.g., WO2009/091601 to Jaiswal et al. at [126], [197] (IDS); Subramanian et al. at Table 1, p. 1806; US2004/0147731 at [0144], Fig. 2A (IDS). CD47 is a known target for human tumor therapy. E.g., Willingham et al., Proc Nat'l Acad Sci 2012; 109:6662-67 (IDS).
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs (or hypervariable regions), which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33 (IDS) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Chimeric antibodies comprise the heavy and light chain variable regions of a rodent antibody linked to human constant regions. Id. at 1619-20. Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4. Almagro provides a detailed discussion regarding various methods of humanization, including rationale design approaches and empirical approaches based on random screening. Almagro, Sections 4 and 5.
Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody that bound a particular antigen, or a particular epitope on the antigen, would look like structurally. The skilled artisan understood that antibodies with diverse structures, from a variety of different sources, may bind the same antigen and even the same general epitope on that antigen, but differ widely in the details of the structure of their antigen-binding sites.
Summary of Species disclosed in the original specification
The specification describes a number of murine antibodies that bind human CD47. E.g., Fig. 1A and 1B. Humanized variants of the 2A1 antibody are described in Example 8. The sequences of the humanized forms of 2A1 are provided in Table 1 at [0120]. Those antibodies share either identical VH-CDR3’s (SEQ ID NO: 52) or their VH-CDR3’s differ by a single amino acid substitution (SEQ ID NO: 77). E.g., [0126]. VL-CDR3 is identical in all of the antibodies in Table 1. E.g., [0127]. The antibodies also share highly similar VH-CDR1, VH-CDR2, VL-CDR1, and VL-CDR2. Antibodies comprising the variant CDRs comprise a VH as set forth in SEQ ID NOS:5-30 and a VL as set forth in SEQ ID NOS: 31-47. The 2A1 antibody and its humanized variants promote macrophage-mediated phagocytosis of tumor cells. E.g., Figure 9 and Example 9.
Examples 12 and 13 look at the effect of isotype and isotype mutations on the activity of one of the humanized antibodies, “AB6.12.” AB6.12 was converted from an IgG1 isotype to IgG4P and IgG4PE isotype variants. The IgG4P Ser228Pro substitution in the hinge was known in the art to improve its stability. The IgG4PE variant has a Leu225Glu substitution in addition to Ser228Pro, which also provides reduced Fc binding. AB06.12 did not cause RBC depletion when administered as IgG4P and IgGPE isotype variants. [0291]. Changing the isotype to IgG4P did not alter the platelet depleting activity of the antibodies. [0289]. But when the FcR binding activity was reduced by adding the L235E mutation to produce IgG4PE, the antibody did not cause platelet depletion. Id., and Figure 12G-H.
In Example 11, the Specification describes the co-crystallization of CD47 with the prior art B6H12 antibody and the 2A1 antibody. In characterizing the binding of the 2A1 antibody to its epitope on CD47, the specification discloses that:
“The VH region of the CD47 antibodies described herein is primarily involved in binding to the KGRD (SEQ ID NO: 56) loop of CD47. Thus, the unique epitope to which antibodies of the present invention bind is on the side of CD47. In contrast to existing CD47 antibodies known in the art, the orientation of the VH domain of the CD47 antibodies described herein in a membrane proximal position is a critical feature of these antibodies that prevents cellular clumping, e.g., red blood cell hemagglutination, by constraining the antibodies such that they cannot bridge to CD47 molecules on adjacent cells. Additionally, because the VK domain of the CD47 antibodies described herein interacts with apical residues such as Y37, TI02, and EI04, which are involved in SIRPα binding, it is primarily the VK domain that physically precludes SIRPα binding to CD47.” Specification at [0041]. See also [0285].
While the language used in the Specification at [0041] generalizes antibodies that bind to this particular epitope, it is only the 2A1 antibody and its humanized variants that appear to actually have this function [0285]. Only “2A1” did not cause agglutination of red cells in an in vitro assay at any of the concentrations tested. E.g. [0250], [0251].
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The only structure required by claim 1 is that of a humanized antibody. But a "humanized" antibody may comprise CDRs from murine or any other species (see [0151] of the specification) in the context of human framework sequences. And for the reasons noted above, the skilled artisan recognized that different CDR combinations lead to different specificities and functional properties. The specification does not describe antibodies that are rat, rabbit, camelid, or any other species of antibody that was known in the art for use in producing humanized monoclonal antibodies. Antibodies produced in different species would have generally been expected to be highly structurally diverse, particularly in the CDR sequences, and would accordingly lead to highly structurally diverse humanized forms of those antibodies. Thus, while applicant has described several species within the genus, the genus is very large and the described species are all highly similar, sharing highly similar CDRs, all derived from a particular mouse antibody. The described species therefore cannot be considered representative of the genus. Regarding claim 15, the Specification has not described any species falling within the genus recited in that claim.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by 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 the claimed genus.
To meet this requirement in the instant case, the specification must have described structural features that convey the claimed functional activities, including binding at the particular epitope recited. As noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody were essential for binding specificity and for functions that flow from that binding. Here, Applicant has provided some insight into which residues within the 2A1 CDRs contribute to binding, but the characterization is limited in that it is in the context of a set of six CDRs that is identical to, or highly similar to, those found in the 2A1 antibody. The claims encompass not only humanized mouse antibodies, but also at least rabbit, rat, and hamster monoclonal antibodies. There is no reason to expect that the mouse antibodies are either representative of the other species of antibodies, or mouse antibodies in general, or that any of those antibodies would share a common structure such as six CDRs. And while the Specification has provided some humanized variants of the 2A1 antibody that contain limited changes in the CDRs relative to the 2A1 parental antibody, it is not clear if those changes do or do not alter the residues contacted within the epitope. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for antibodies other than those comprising all six CDRs of the 2A1 antibody in the context of human VH and VL chains.
And with respect to claim 15, because the 2A1 antibody does not appear to have the recited function, even where the claims limited to the CDRs to 2A1, there would still not be a clear structural correlation that would provide the binding orientation and positioning recited in claim 15.
When determining the representative examples and the art, it is important to consider whether there is evidence of a singular shared structural feature which imparts the defining property of the claimed genus, and which would necessarily be present in every species of the claimed genus. Specifically, the physical features (or amino acid residues encoding said features) which impart the property of “humanized variable domains binding the discontinuous epitope of CD47 and wherein the antibody does not cause agglutination of red blood cells”, should be disclosed. Such a description would be essential in determining the degree of variability that may be allotted in total structural identity. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants (anti-CD47 antibodies with different CDRs or different humanization sequences) would be anticipated, a priori, by one skilled in the art to fall within the scope of the claims.
Conclusion
For all of the reasons presented above, one of skill in the art would not know which of the countless other humanized monoclonal antibodies (from which other sources, with which other CDRs) that met the highly general structural requirements of the claims would also meet the functional limitations of the independent claim. In this case, all of the species that are described and that have the claimed functions are chimeric, humanized, or optimized humanized variants of the same antibody, the “2A1” antibody. All of those antibodies utilize highly similar sets of six CDRs in the context of human VH and VL domains. Neither does Applicant provide a structure common to the member of the genus (beyond the genus of antibodies that share the CDRs of the described 2A1 humanized antibodies, in the context of antibody VH and VL chains, which have been previously allowed). The epitope bound is not a structure shared by the antibodies; it is a recitation of a binding function that is desirably possessed by the antibody (i.e., the desired antibody binds by making contact at particular amino acids on the antigen). The disclosure of residues bound on the antigen do not dictate the structure of the antibodies within the genus and do not permit the skilled artisan to visualize or recognize the members of the genus of antibodies that would bind that epitope. Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of antibodies as broadly claimed. Given the lack of a recitation of shared structural properties that would be expected to provide the claimed functional activities, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, claims 1-20 are rejected for lack of adequate written description support.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,045,541 (IDS) in view of Chao et al., (from IDS, Cite No. 200; Cell 142:699-713 (2010)). Although the claims at issue are not identical, they are not patentably distinct.
The claims of the ‘541 recite antibodies defined by SEQ ID NOS that are the same as the antibodies disclosed as the working embodiments of the instant application and used to provide the basis for support for the current genus claims. The antibodies claimed in the ‘541 therefore must necessarily have the same functional properties as recited in the instant claims.
However, the patented claims do not recite a method of treating a hematological cancer by administering the antibody as required by the instant claims.
Chao teaches that anti-CD47 antibody therapy synergizes with the anti-CD20 antibody Rituximab for treatment of the hematological cancer non-Hodgkin’s lymphoma (NHL). E.g., Abstract. The ordinary artisan would have therefore found it obvious to substitute the antibody of the patented claims for the anti-CD47 antibody of Chao in the method of treating NHL. Given that both antibodies bound CD47 and enhance phagocytosis, the ordinary artisan would have had a reasonable expectation that the anti-CD47 of the patented claims could also synergize with rituximab for treating NHL.
Therefore, the claims are not patentably distinct.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 9,663,575 (IDS). Although the claims at issue are not identical, they are not patentably distinct.
The claims of the ‘575 recite methods of alleviating cancer by administering antibodies defined by SEQ ID NOS that are the same as the antibodies disclosed as the working embodiments of the instant application and used to provide the basis for support for the current genus claims. The antibodies claimed in the ‘575 have the same functional properties as recited in the instant claims and, as recited in patented claims 17-19, they bind the same epitope as recited in the instant claims. Claim 21 recites that the cancer is a hematological cancer. Patented claims 7 and 8 recite further administering additional therapies. Accordingly, the claims are not patentably distinct.
Conclusion
No claims are allowed.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642