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 .
DETAILED ACTION
Applicant’s election without traverse of Group I, claims 27-48, as well as IM1240 as a species of tri-specific antibody, in the reply filed on 12/12/2025 is acknowledged.
Claims 27-48 are pending.
Claims 40 and 41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/12/2025.
Claims 49-52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/12/2025.
Claims 27-39 and 42-48 are under examination on the merits.
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 claims have an earliest effective filing date of 05/04/2020, corresponding to application PRO 63/019,443.
Information Disclosure Statement
The Information Disclosure Statements filed on 03/02/2023, 10/02/2023, 10/02/2023, 12/19/2024, 04/01/2025, and 12/12/2025 have been considered.
Notes on the Prior Art
The elected species IM1240 comprising SEQ ID NOs: 623 and 624 (anti-5T4), 635 and 639 (anti-NKG2A), and 457 and 461 (anti-CD3) in the reply filed on 12/12/2025 is acknowledged. Following a sequence search, it has been determined that the elected species is free of the prior art.
Specification
The specification is objected to because of the following informalities: The specification contains URLs at paragraph 0433. Appropriate correction is required.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 27-32, 37-39, and 42-48 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al (WO2020084608; published 04/30/2020) in view of Spee et al (WO 2008/009545, international publication date: 01/24/2008).
Zhou et al teach a precursor bispecific antibody comprising binding domains against a tumor associated antigen and a CD3, a regulatory domain comprising a cleavable half-life prolonging (HLP) domain comprising a protease cleavage domain (Zhou et al, paragraph 0013). Zhou et al also teach the regulatory domain may comprise a CAP component (Zhou et al, paragraph 0015). Additionally, Zhou et al teach the TAA binding domain may be an scFV and the CD3 binding domain may be a Fab (Zhou et al, paragraph 0018).
Therefore Zhou et al teach a precursor bispecific antibody and antibody comprising a TAA binding domain, CD3 binding domain, and regulatory domain. Zhou et al do not teach a trispecific precursor antibody and antibody comprising a TAA binding domain, an NK cell binding domain, a T-cell binding domain, and a regulatory domain. This deficiency is remedied by Spee et al.
At p. 1, Spee et al teach that “[a]ntibodies that inhibit CD94/NKG2A may increase the cytolytic activity of tumor-specific lymphocytes against tumor cells. Therefore, therapeutic antibodies that inhibit CD94/NKG2A in cancer patients without killing CD94/NKG2A-expressing cells may be able to control tumor-growth.” At p. 2, final paragraph, Spee et al teach that anti-NKG2A antibodies may be used in the treatment of cancer. At p. 22, Spee et al. teach that anti-NKG2A antibodies may be comprised within trispecific antibodies that comprise, for example, an anti-CD3-binding moiety that binds to a triggering molecule on T cells to focus cellular defense mechanisms to NKG2A-expressing cells.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Zhou et al with those of Spee et al to arrive at a trispecific precursor antibody and antibody comprising a TAA binding domain, an NK cell binding domain, a T-cell binding domain, and a regulatory domain. One of ordinary skill in the art would have been motivated to do so because Zhou et al teach a precursor bispecific antibody and antibody comprising a TAA binding domain, CD3 binding domain, and regulatory domain. Furthermore based upon the teachings of Spee et al, one of ordinary skill in the art would have been motivated to treat cancer with an NKG2A scFv, and Spee et al. teach that anti-NKG2A antibodies may be comprised within trispecific antibodies that comprise, for example, an anti-CD3-binding moiety that binds to a triggering molecule on T cells to focus cellular defense mechanisms to NKG2A-expressing cells. As such one of ordinary skill in the art would have been motivated to modify the invention of Zhou et al, which teaches a bispecific antibody for a TAA and CD3, to further include an NKG2A binding domain because there would have been a reasonable expectation that the resultant invention, which comprises the administration of a trispecific antibody, is effective in treating cancer. The invention of Zhou et al and Spee et al meets the limitations of claims 27, 28, 29, 37, and 38.
Regarding claims 30, 31, 32, and 39 Zhou et al teach the TAA may be 5T4 (Zhou et al, paragraph 0018).
Regarding claim 42, Zhou et al teach variations for the order of the antibody construct (Zhou et al, paragraph 0013-0017).
With respect to claim 43, one of ordinary skill in the art would appreciate that the invention of Zhou et al and Spee et al could be prepared such that the protease cleavage domain, the HLP domain, and the CAP domain could be positioned either C- or N-terminally to the VH and VL of the third binding domain.
Regarding claims 44-45, Zhou et al teach a pharmaceutical composition (Zhou et al, paragraph 0076)
Regarding claims 46 and 48, Zhou et al teach nucleic acid sequences encoding the constructs (Zhou et al, pg. 166, claim 19).
Regarding claim 47. Zhou et al teach an expression vector comprising the nucleic acid sequences (pg. 166, claim 20).
Therefore the claims were prima facie obvious at the effective filing date of the invention.
35 USC § 112(a)
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 27-34, 37-39, and 42-48 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Claim 27 is drawn to a precursor tri-specific antibody construct, comprising:(a) a first binding domain that binds to a tumor associated antigen (TAA); (b) a second binding domain that binds to a first natural killer (NK) cell surface antigen or a second binding domain comprising a cytokine receptor engager; (c) a third binding domain that binds to a T cell surface antigen or a second NK cell surface antigen; and (d) a regulatory domain comprising a protease cleavage domain, a half-life prolonging (HLP) domain, and a CAP component that reduces the ability of the third binding domain to bind to its target antigen.
Applicants elected a trispecific antibody comprising anti-5T4, anti-NKG2A, and anti-CD3.
The claims encompass a large number of tri-specific antibodies having diverse heavy and light chain CDR amino acid sequences. Following a review of the specification, it appears that Applicant has disclosed seven anti-5T4, anti-NKG2A, and anti-CD3 binding domains, specifically IM1236-IM1242. However in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to encompass multiple anti-5T4, anti-NKG2A, and anti-CD3 binding domains having diverse heavy and light chain CDR sequences. Even though Applicant has disclosed seven species within said genus, the specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequences (and combinations of said CDR sequences) give rise to antibody molecules capable of binding anti-5T4, anti-NKG2A, and anti-CD3. As detailed below Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
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.
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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. In the instant case, Applicant has disclosed seven species within the genus claimed. However given the substantial antibody structure variation within the genus, the disclosure of seven species comprised within the claimed genus is not sufficiently representative of the entire genus.
Furthermore Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences (or combinations thereof) that confer upon an antibody the ability to bind 5T4, NKG2A, and CD3, because the instant specification does not provide structural antibody features that correlate with a functional ability to bind 5T4, NKG2A, and CD3. To elaborate on why the claimed antibodies lack adequate written description, Mariuzza (Annu. Rev. Biophys. Biophys. Chem., 16: 139-159, 1987) reviews the structural basis of antigen-antibody recognition and teach that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure that fully comprises six CDRs, three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of the antibody’s antigen-binding specificity. In view of Mariuzza, it is apparent that antibodies having less than all six CDRs that form the antigen binding site of a conventional antibody in their proper context of heavy and light chain variable domains do not describe the particularly identifying structural feature of the antibody that correlates with the antibody’s ability to bind antigen. Absent a description of the at least minimal structural features correlating with a functional ability to bind 5T4, NKG2A, and CD3 which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences (or combinations thereof) may be combined such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to bind 5T4, NKG2A, and CD3.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to bind 5T4, NKG2A, and CD3, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
Accordingly given the unpredictability associated with antibody CDR region changes on antigen binding and given the lack of particularity with which the claimed antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed.
Applicant is informed that this rejection may be overcome by amending claim 27 to include the limitations of claim 35 or 36.
Allowable Subject Matter
Claims 35 and 36 are 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
No claim is allowed.
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/J.K.D./Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642