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 .
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 24-26, 36-38 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brogdon et al (US 20160096892 A1).
Brogdon et al teach CAR proteins, cells and nucleic acid constructs comprising two different CARs separated by two or more cleavage sites (¶ [0575] –[0576], Table 20). The CAR molecules of Brogdon et al comprise antigen binding domains, transmembrane domains and intracellular signaling domains (e.g. Fig. 3). Claims 25 and 37 describe both possible placements of the cleavable domains. Pharmaceuticals comprising the cells are taught in ¶ [0745] and the disclosed cells are taught to be a treatment for cancer, including hematological cancers (Title, ¶’s [0060]-[0061]). The CARs can be expressed from plasmids in (¶ [0053]) in the orientation described in claim 38 (¶ [0575]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fry et al (WO 2016/149578, of record) in view of Ma et al (WO 2016/210293, of record).
Fry et al teach a bispecific CAR construct targeting CD22 and CD19. More specifically, the CAR comprises an anti-CD22 antigen binding domain, an anti-CD 19 antigen binding domain, a hinge domain, a transmembrane domain, and an intracellular T cell signaling domain (claim 1), wherein the anti-CD22 antigen binding domain comprises the amino acid sequences of SEQ ID NO: 1-6, (claim 2) or wherein the anti-CD 19 antigen binding domain comprises the amino acid sequences of SEQ ID NO: 7-12 (claim 3) wherein the anti-CD22 antigen binding domain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14 (claim 4). SEQ ID Nos 1-6, 13 and 14 are the CDR and variable region sequences of antibody m971 respectively. SEQ ID Nos 7-12, 15 and 16 are the CDR and variable region sequences of antibody FMC63, respectively.
Fry et al do not teach two CARs separated by a cleavage domain.
Ma et al teach cells comprising a first and second CAR polypeptides comprising different antigen binding domains (claim 1), wherein the first and second CARs are on a single polypeptide molecule. An amino acid sequence comprising a high efficiency cleavage site is disposed between the first and second CAR polypeptides (claim 2), wherein the high efficiency cleavage site is selected from the group consisting of P2A, T2A, E2A, and F2A (claim 3).
The claimed CARs are essentially disclosed by Fry et al with the exception of the cleavage site limitation. The ordinary skilled artisan, seeking to create CAR molecules for cancer treatment methods, would have been motivated to use the dual CAR cleavage system with the specific CAR antigen binding domains of Fry et al because both Fry and Ma et al teach the desirability of expressing bispecific or dual-specific CARs. It would have been obvious for the skilled artisan to do this because of the known benefit of improving CAR-mediated therapy as taught by Fry and Ma et al. Given the teachings of the cited references and the level of skill of the ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
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.
Claim 23 is 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding, binding to a certain epitope), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Along these same lines, a more recent Federal Circuit decision, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describes how when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself not just a description of the sequence to which the antibody binds. Amgen, 872 F.3d at 1378-79.
The importance of this court decision was recently expounded upon by Robert W. Bahr, Deputy Commissioner for Patent Examination Policy in a memorandum clarifying the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) as it relates to claims drawn to antibodies (see Memorandum of February 22, 2018, 2 pages, https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf).
Specifically, the so-called “newly characterized antigen” test, which had been based on an example in previously issued USPTO training materials and had been used in the past for determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody is now considered defunct.
The Memorandum explains that USPTO personnel should continue to follow the relevant sections of the MPEP pertaining to the written description requirement of 35 U.S.C. § 112(a) (without regard for any disclosure in the MPEP concerning the use of a fully characterized antigen to provide written description support for an antibody to said antigen).
As described in MPEP § 2163, “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…reduction to drawings…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…See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
Note well: even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
In the instant case, the claims are drawn to CARs comprising at least 90% sequence identity to SEQ ID NOs: 63-70, meaning that the VH and/or VL domains can have up to 75 amino acid changes (all of the SEQ ID NOs are ~750 residues), wherein all of the changes occur within the light and heavy chain CDR regions of the CARs.
However, the teachings of the instant specification are insufficient to establish possession of the breadth of polypeptides comprising a CAR having at least 90% sequence identity to SEQ ID NOs 63-70 that can have up to 75 amino acid changes, wherein all of the changes occur within the heavy and light chain CDR regions of the CAR, as encompassed by the instant claims.
Any number of VH and VL CDR residues are expected, a priori, to contribute to antigen binding and yet the instant specification and the knowledge in the art do not establish which residues of the disclosed VH and VL CDRs are structurally essential to antigen binding versus those that are tolerant to change, and to what degree, i.e., conservative or radical.
To illustrate this point, consider Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28, cited herewith) which teaches “[t]he specificity and affinity of an antibody for its cognate antigen is determined by the sequence and structure of the variable fragment (Fv): a heterodimer consisting of the N-terminal domains of the heavy and light chains. Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.” (see, page 416, column bridging paragraph, emphasis added).
Vajdos goes on to teach that "[b]y analyzing panels of point mutants, a detailed map of the binding energetics can be obtained, but the process can be very laborious because individual mutant proteins must be made and analyzed separately. In particular, a comprehensive analysis of an antigen binding site would ideally encompass all CDR residues, and this would require the analysis of dozens or even hundreds of point mutants." (see page 416, right column, first paragraph). Vajdos solution to this dilemma was to make use of a shotgun scanning mutagenesis which "uses phage displayed libraries of protein mutants constructed using degenerate codons with restricted diversity." While this method of making libraries of mutants representative of the potential antigen binding CDR residues was an improvement over previous strategies as taught by Vajdos, it nonetheless required extensive experimentation to comprehensively scan the potential CDR sequence space (see page 416, right column, 2nd paragraph and pages 425-427, Materials and Methods.)
Furthermore, even after performing this comprehensive scanning mutagenesis of all CDR
residues from the particular anti-ErB2 antibody under study, Vajdos would still not have been
able to say which CDR residues were actually involved in antigen binding, and which were
involved in stabilizing the secondary and tertiary structure of the CDRs within the context of the
heavy and light chains as a whole, without the structure of the unbound antigen-binding site of
the antibody to aid in their analysis (see, in particular, Discussion, pages 422-425).
Rather, Vajdos needed to perform not only a comprehensive shotgun scanning mutagenesis of all CDR residues of the antibody under study, but also needed a structure of the unbound antigen binding site in hand to gain a sufficient understanding of the contribution of each CDR to antigen-binding to adequately predict which CDR residues can be changed, and to what extent, or in what context of additional compensatory mutations in other regions of the antibody.
Moreover, given an amino acid substitution that ablated binding, without the crystal structure in hand, still further experimentation would have been required to determine the flexibility in this particular residue, i.e., it's general tolerance or intolerance to change.
As yet another example to illustrate the sensitivity of some antibodies to changes in their CDR residues, especially CDR3, consider the teachings of Bedouelle et al. (FEBS J. 2006 Jan;273(1):34-46, of record). While Bedouelle did not comprehensively scan all the CDR residues of their antibody using a combination of alanine and homologous substitutions as shown in Vajdos, Bedouelle did examine the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a >100 fold drop in binding affinity (see Table 1). As described by Bedouelle, some of these loss of function mutations were hypothesized to have a direct effect on antigen binding while others were hypothesized to indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section). Thus, the teachings of Bedouelle provide further illustration of the unpredictability of making mutations within the CDR region of an antibody.
Notably, while the teachings of Vajdos and Bedouelle demonstrate the unpredictable effects of even single amino acid changes on antibody:antigen binding, there is an additional level of unpredictability in the art associated with making multiple changes in any given CDR(s).
In particular, even in those instances where one can show certain residues of a given CDR are generally tolerant of single amino acid changes, this does not necessarily mean a combination of single amino acid changes, even to the same residues shown to tolerate change when mutated in isolation, will be tolerated. As an example consider Brown et al. (J Immunol. 1996 May 1;156(9):3285-91, of record) which describes how the VH CDR2 in a particular antibody was generally tolerant of single amino acid changes; however, the antibody lost binding upon the introduction of pairs of single amino changes in the same region (see, in particular Tables I and II and column bridging paragraph on page 3290).
Given the above the skilled artisan cannot extrapolate from the disclosure of the instant specification to establish possession of the breadth of CAR variants encompassed by the instant claims.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibody-like binding molecules because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of CAR molecules.
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, 9, 24-26, 36-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 9, 11, 12 and 13 of U.S. Patent No. 11,980,640. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are genus claims anticipated by the ‘640 claims, or are methods used to prepare the vector and cells of the ‘640 claims. It is noted that the SEQ ID NOs in claim 1(i) of ‘640 inherently encode an m971 antibody and the SEQ ID NOs of claim 1(ii) encode the FMC63 antibody.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael Burkhart whose telephone number is (571)272-2915. The examiner can normally be reached M-F 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL D BURKHART/Primary Examiner, Art Unit 1638
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