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 an anti-NKG2A antibody as a species of NK inhibitory ligand in the reply filed on 10/02/2025 is acknowledged.
Claims 1-13, 16, 20-26, 28, 30, and 32-34 are pending.
Claims 9-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 10/02/2025.
Claims 1-8, 12, 13, 16, 20-26, 28, 30, and 32-34 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. Claims 1-8, 12, 13, 16, 20-26, 28, 30, and 32-34 have an effective filing date of 06/11/2020, corresponding to CN202010527572.0.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/08/2022, 11/14/2023, and 10/18/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objection to the Specification
At [00178] of the specification, it is stated that SEQ ID NO(s) 57/58 and 59/60 correspond to anti-LIR1 scFv molecule; however the Sequence Listing, dated 01/19/2023, indicates that these SEQ ID NO(s) correspond to an anti-KIR scFv. Appropriate correction is required.
Claim Rejections
35 U.S.C. 112(b)
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.
Claims 8 and 11 recite various polypeptides that are “represented by” various SEQ ID NO(s). There is not well-settled definition in the art of what constitutes a representative of a particular SEQ ID NO. As such one skilled in the art would be unable to readily delineate the metes and bounds of the claims. This issue may be remedied by replacing the recitation of “as represented by” with “comprising.”
Regarding claim 11, the term “preferably” and the phrase “more preferably” both render the claim indefinite because it is unclear whether the limitation(s) following said term and phrase are part of the claimed invention. See MPEP § 2173.05(d).
35 U.S.C. 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 1-7, 12, 13, 16, 20-26, 28, 30, and 32-34 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 1 is drawn to an NK inhibitory molecule comprising one or more NK inhibitory ligands, a transmembrane domain, and a co-stimulatory domain, wherein the one or more NK inhibitory ligands specifically bind to NK inhibitory receptors (NKIR) to inhibit killing of NK cells against an engineered immune cell expressing the NK inhibitory molecule, wherein the NK inhibitory molecule does not contain an intracellular signaling domain, and claim 20 is drawn to an engineered immune cell that expresses said NK inhibitory molecule. Following a review of the specification, the following NK inhibitory molecule species have been adequately described in the Examples:
an NK inhibitory molecule comprising a NK inhibitory ligand that is the extracellular region of E-cadherin comprising SEQ ID NO: 41,
an NK inhibitory molecule comprising a NK inhibitory ligand that is the extracellular region of HLA-E comprising SEQ ID NO: 33,
an NK inhibitory molecule comprising a NK inhibitory ligand that is the extracellular region of HLA-G comprising SEQ ID NO: 35,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-NKG2A scFv comprising SEQ ID NO(s): 5 and 7,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-KIR scFv comprising SEQ ID NO(s): 55 and 56,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-SIGLEC7 scFv comprising SEQ ID NO: 130,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-SIGLEC7/SIGLEC9 scFv comprising SEQ ID NO: 184,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-KLRG1 scFv comprising SEQ ID NO: 119, and
an NK inhibitory molecule comprising a NK inhibitory ligand that is the extracellular region of PDL1 comprising SEQ ID NO: 33.
However in view of this disclosure, Applicant is claiming a broad genus of NK inhibitory molecules comprising different NK inhibitory ligands. Even though Applicant has disclosed nine 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 NK inhibitory ligands give rise to NK inhibitory molecules. 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 nine species within the genus claimed; however given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of nine species comprised within the claimed genus is not sufficiently representative of the entire genus.
Furthermore the specification does not disclose relevant, identifying characteristics of NK inhibitory ligands that are appropriate for use in NK inhibitory molecules. While some inhibitory NK ligands bind to NK inhibitory receptors (NKIRs) to reduce NK activation, in other instances, for example, when the KIR of a donor cell and a recipient HLA-B and -C (NKIRs) are mismatched, NK activation is facilitated - “KIRs are polymorphic type 1 trans-membrane molecules present on certain subsets of lymphocytes, including NK cells and some T cells. KIRs interact with determinants in the alpha 1 and 2 domains of MHC class I molecules. In patients with AML, haplo-identical stem cell transplantation (SCT) can lead to expansion and activation of KIR-HLA class I mismatched NK cells, resulting in reduced rates of leukemia relapse, no graft-versus-host disease, and markedly improved survival rates (Ruggeri et al., Science 2002;295:2029-31 ). The molecular basis for the clinical efficacy of haplo-identical SCT is that NK cell-mediated tumor killing is regulated by inhibitory KIR receptors. Upon binding to their specific HLA-B or -C ligands, these NK cell receptors transmit negative signals which inhibit NK cell-mediated killing of tumors. As HLA-B and -C molecules are highly polymorphic in the population, and distinct HLA allotypes are recognized by either KIR2DL1 or by KIR2DL2/3, it is often possible to find donors and recipients who KIR and HLA are mismatched, i.e., where the KIR of the donor do not bind an HLA ligand in the recipient. In such situations, there is no transmission of inhibitory signals via the KIR that fail to bind HLA ligands, facilitating activation of NK cells.” See p. 2 of Wagtmann et al. (WO 2008/084106, internation publication date: 07/17/2008). Furthermore Example 13 demonstrates that anti-KIR antibodies are capable of activating NK cells in cancer patients.
Moretta et al. (US 2009/0208416, publication date: 08/20/2009) teach that while some monoclonal antibodies against NKG2A are inhibitory, others activate NK cells - “[0015] The present invention provides monoclonal antibodies and fragments thereof directed against the NKG2A receptor. The monoclonal antibodies and fragments thereof of this invention may either inhibit the ability of NK cells to lyse normally susceptible target cells (‘NK cell inhibitory antibodies’) or reconstitute the ability of NK cells to lyse otherwise protected target cells (‘NK cell activating antibodies’).” See [0015]. “Without being bound by theory, the inventors believe that the presence of an Fc receptor binding region in the antibodies and fragments of this invention causes inhibition of NK cell lysis in the presence of a cell bearing an Fc receptor. Those antibodies and fragments that lack an Fc receptor binding region are capable of reconstituting NK cell lysis of target cells bearing HLA-E or Qa1b on their cell surface.” See [0017]. This is a significant teaching, because Example 1 describes the preparation of an NK inhibitory molecule comprising an anti-NKG2A scFv, which does not comprise an Fc region. Therefore the teachings of Moretta et al. suggest that such an anti-NKG2A scFv would be lead to NK activation, rather than inhibition.
Monroe et al. (WO 2017/040301, international publication date: 03/09/2017) suggest that anti-Siglec-7 antibodies may be either activating or inhibitory - “An ‘agonist’ antibody or an ‘activating’ antibody is an antibody, such as an agonist anti-Siglec-7 antibody of the present disclosure, that induces (e.g., increases) one or more activities or functions of the antigen after the antibody binds the antigen… A ‘blocking’ antibody, an ‘antagonist’ antibody, or an ‘inhibitory’ antibody is an antibody, such as an anti-Siglec-7 antibody of the present disclosure, that inhibits or reduces (e.g., decreases) antigen binding to one or more ligand after the antibody binds the antigen, and/or that inhibits or reduces (e.g., decreases) one or more activities or functions of the antigen after the antibody binds the antigen. In some embodiments, blocking antibodies, antagonist antibodies, or inhibitory antibodies substantially or completely inhibit antigen binding to one or more ligand and/or one or more activities or functions of the antigen.” See [0094].
Based upon these references, it is clear that absent a description of the at least minimal structural features correlating with a functional ability to inhibit NK cell function which are shared by members of a genus commonly sharing this function, the skilled artisan could not immediately envision, recognize, or distinguish which NK inhibitory ligands give rise to NK inhibitory (and not activating) molecules.
Although screening techniques can be used to isolate NK inhibitory ligands that give rise to NK inhibitory molecules, 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 NK cell inhibition and given the lack of particularity with which the claimed NK inhibitory molecules 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 the rejection of the claims under 35 U.S.C. 112(a) may be overcome by amending the independent claims to recite one or more of the following:
an NK inhibitory molecule comprising a NK inhibitory ligand that is the extracellular region of E-cadherin comprising SEQ ID NO: 41,
an NK inhibitory molecule comprising a NK inhibitory ligand that is the extracellular region of HLA-E comprising SEQ ID NO: 33,
an NK inhibitory molecule comprising a NK inhibitory ligand that is the extracellular region of HLA-G comprising SEQ ID NO: 35,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-NKG2A scFv comprising SEQ ID NO(s): 5 and 7,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-KIR scFv comprising SEQ ID NO(s): 55 and 56,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-SIGLEC7 scFv comprising SEQ ID NO: 130,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-SIGLEC7/SIGLEC9 scFv comprising SEQ ID NO: 184,
an NK inhibitory molecule comprising a NK inhibitory ligand that is an anti-KLRG1 scFv comprising SEQ ID NO: 119, and
an NK inhibitory molecule comprising a NK inhibitory ligand that is the extracellular region of PDL1 comprising SEQ ID NO: 33.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642