DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
2. The information disclosure statements (IDS) submitted on 10/26/2023 and 04/10/2026 are acknowledged and the references cited therein have been considered.
Priority
3. The present application is a 371 National Stage Application of PCT International Application No. PCT/CN2022/089287, filed 04/26/2022, which claims the benefit of Chinese Patent Application No. CN202110462389.1, filed 04/27/2021. Applicant' s claim for the benefit of prior-filed application is acknowledged.
Status of Claims
4. Applicant’s preliminary amendments received 10/26/2023 and 11/01/2023 are acknowledged.
5. Claims 1, 3, 7, 18-20, 27-28, 34-35, 38-39, 44-45, 54, 56, 58, 65, 68, and 75 are pending in the instant application.
6. Applicant’s election of Group I, claims 1, 3, 7, 18-20, 27-28, 34-35, 38-39, 44-45, 54, 56, and 68, with traverse, is acknowledged, which is directed to a chimeric antigen receptor (CAR), comprising a BCMA (B cell maturation antigen) binding domain, said BCMA binding domain comprising an antibody or antigen-binding fragment of an antibody that specifically binds to BCMA.
7. Applicant’s traversal is on the grounds that the Office has not shown that the burden imposed on the Office in examining Groups I to III together would be serious. This is not found persuasive because the specific Groups are comprised of polypeptide antibodies/CARs versus nucleic acid/effector cell that are recognized divergent subject matter. In addition, the different inventions are distinct because their structures are different and are therefore capable of separate manufacture, use and sale. Therefore the Groups are distinct and independent, and searches of all Groups would place an undue burden upon the examiner due to the distinct and divergent subject matter of each Group. Further, a prior art search also requires a literature search. It is an undue burden for the examiner to search more than one invention.
The requirement is still deemed proper and is therefore made FINAL.
8. Claims 58 and 65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
9. Applicant’s election of the species of: A) hBCMA-19 CDRs. hBCMA-20 CDRs, hBCMA-22 CDRs, hBCMA-23 CDRs, with VH and VL sequences of hBCMA-22 (VH SEQ ID NO: 9, VL SEQ ID NO: 4); B) CD8 Transmembrane domain; C) CD137 costimulatory domain; D) hBCMA-22 CAR (SEQ ID NO 70) and hBCMA-22-L6-Li CAR (SEQ ID NO 74); and E) multiple myeloma, filed in the response on 05/26/2026, are acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
10. Claims 44 and 45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The recitations of the phrase "derived from" in claims 44 and 45 are indefinite because it is unclear what changes or how many changes could have occurred to result in a derivative. Derivation only describes the source and not the result.
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.
Written Description
11. Claims 1, 3, 7, 18-20, 27-28, 34-35, 44-45, 54, 56, 68, and 75 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.
The scope of the claim 1 broadly encompasses antibodies binding BCMA with less than 6 intact CDRs and modifications to HCDR2 (e.g., SEQ ID NO: 41) at amino acid positions 10 and 17.
Claims 3, 7, 18, and 19 are included because they depend from claim 1 and still recite less than 6 intact CDRs.
Claim 20 depends from claim 1 and encompasses antibodies binding BCMA with LCDRs 1-3 (e.g., SEQ ID NOs: 38, 39, and 40) which all 3 contain amino acid modifications.
Claim 27 encompasses the CAR of claim 20 and recites mixing and matching 6 intact CDRs.
Claim 28 is included because it depends from claim 20, which depends from claim 1.
Claim 34 is included because it depends from claim 1 and encompasses a VL (e.g., SEQ ID NO: 45) which contains amino acid modifications.
Claim 35 is included because it depends from claim 34, which depends from claim 1.
The specification and species election provides four anti-BCMA antibodies, hBCMA-19, hBCMA-20, hBCMA-22, and hBCMA-23, which were not random combinations of VH and VL i.e., they had specific VH domain (SEQ ID NO: 9) paired with specific VL domain (SEQ ID NO: 4, respectively). No other VH/VL domain was provided that mix the CDRH1 of SEQ ID NO: 21, CRRH2 of SEQ ID Nos: 22 or 24, or CDRH3 of SEQ ID NO: 25 or CDRL1 of SEQ ID NO: 12, CDRL2 of SEQ ID NO: 13 or 14, and CDRL3 of SEQ ID NO: 16. The specification and species election discloses only four species within the instant claim scope. There is no teaching identifying what amino acids can be varied within the VH-CDRs and/or VL-CDRs antibody regions and still retain antibody or fragments capable of binding space domain of BCMA. Brown et al (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. 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. The scope of the claims encompasses antibodies with VH or VL that encompass variation (addition, deletion, substitution) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g. 6CDR's) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VLCDRs or VHCDRs regions of the disclosed antibody and the retention of a specific binding antibody that binds the BCMA to satisfy the WD requirement for the claims.
Neither the specification, nor the prior art provides any examples to support the premise of mixing and matching a HCDR or LCDR of the VH/VL of different antibodies would result in antigen binding. The prior art does not support a definition of an antibody structure by mixing and matching the HCDR1-3 sequence of a VH and/or LCDR of sequence of a VL and result in functional anti-BCMA antibody. The specification fails to show that all HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3 of the anti-BCMA antibodies, hBCMA-19, hBCMA-20, hBCMA-22, and hBCMA-23, are equivalent. For example, the clones all have different cytotoxicity (see Figure 4). The specification fails to establish that by replacing at least one CDR of hBCMA-22 antibody with another CDR from hBCMA-19, hBCMA-20, or hBCMA-23, maintains BCMA binding. Mixing and matching different the CDRs from different anti-BCMA antibodies has not been shown to lead to BCMA binding. Such teachings were not made part of the specification at the time the invention was made.
The claims also encompass antibodies in which modification of the amino acids may vary in either or both the VH CDRs and/or VL CDRs region of SEQ ID NOs: 41 and 38, 39, and 40 via addition, deletion, substitution or insertion of one or more amino acids.
It is unlikely that antibodies or fragments thereof as defined by the claims which may contain less than the full complement of CDRs from the heavy and light chain variable regions of the hBCMA-19, hBCMA-20, hBCMA-22, and hBCMA-23 antibody fused to framework sequence, have the required binding function. The specification provides no direction or guidance regarding how to produce monoclonal antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone. Further, the specification does not teach that a functional antibody can be obtained by replacing the CDR regions of an acceptor antibody with the less than all the 6 CDRs sequences of a donor antibody.
With respect to the recitation an antibody which does not comprise all 6 CDRs, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material ((https://www.aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Given the well-known high level of polymorphism of antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of antibodies encompassed in the claims at the time the instant application was filed.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
Enablement
12. Claim 75 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating multiple myeloma with a CAR comprising anti-BCMA antibodies recited in claim 38, does not reasonably provide enablement for more diseases or disorders associated with BCMA expression. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The claim encompasses the treatment of each and every disease or disorder associated with BCMA expression with a CAR comprising anti-BCMA antibodies.
The specification does not provide exemplification of animal model to treat each and every disease or disorder associated with BCMA expression with a CAR comprising anti-BCMA antibody.
Besides multiple myeloma, no effect of any therapy was administered to each and every disease or disorder associated with BCMA expression with a CAR comprising anti-BCMA antibodies.
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are drawn to the treatment of each and every disease or disorder associated with BCMA expression with a CAR comprising anti-BCMA antibodies.
The experiments in the specification never successfully used the CAR comprising anti-BCMA antibodies to treat each and every disease or disorder associated with BCMA expression.
In the instant specification, the only BCMA-expressing cell line used in the in vitro and in vivo experiments is the human multiple myeloma cell line MM1s (see Example 6 paragraph [00251], example 8 paragraph [00279], etc.). Thus there is a lack of sufficient working examples for the breadth of the claim.
Furthermore, regarding in vivo methods which rely on generally unpredictable mechanisms, ''The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.'' In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction'' refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (MPEP 2164.03).'' The MPEP also states that physiological activity can be considered inherently unpredictable.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Allowable Subject Matter
13. Claims 38-39 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
14. No claims are allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALAN ALFANO whose telephone number is (571)272-3092. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALAN ALFANO/Examiner, Art Unit 1641
/MAHER M HADDAD/ Primary Examiner, Art Unit 1641
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