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 .
Status of Claims
Claims 9-14, 16-20, 22-25, 27, 41, 44, 46, 50, 58 are amended. Claims 15, 21, 26, 28-40, 42-43, 47-49, 51-57, and 59-93 are cancelled. Claims -----9-14, 16-20, 22-25, 27, 41, and 44-46 are currently under examination.
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 09/19/2019 corresponding to application PRO 62/902,741.
Information Disclosure Statement
The Information Disclosure Statements filed on 11/22/2022, 07/06/2023, 08/25/2023, 12/27/2023, 01/16/2024, 02/27/2024, 03/15/2024, 06/07/2024, 10/21/2024, and 09/04/2025 have been considered.
Election/Restrictions
Claims 50 and 58 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 09/04/2025.
Applicant’s election without traverse of 068744_E31S in the reply filed on 09/04/2025 is 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.
Regarding claim 19, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims -----9, 11-14, 16-20, 22-24, and 27 recites the broad recitation “or”, and the claim also recites “and” which is the narrower statement of the range/limitation. The specification defines “the use of “or” to mean “and/or” unless otherwise stated” (Instant application, Detailed Description section, paragraph 1). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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 -----9, 11-13, 16, 18-20, 22-25, 27, 41, and 44-46 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 9 is drawn to a binding domain, e.g. an antibody that binds hVISTA, wherein the antibody comprises:
a heavy chain variable region comprising VH complementarity determining region CDR1, CDR2 and CDR3 of P1-068744_E31S, P1-68744_H501, P1-68744_E59Y,P1- 068744_E100S, P1-068744_E102Y, P1-068744_E31SH501, P1-068744_H501_E59Y,P1- 068744_E59YE100S, P1-068744_E100SE102Y, P1-068744_E31SE102Y P1- 068744 E31S E59Y, P1-068744 E31S E100S, P1-068744 H50IE100S, P1-068744_H50IE102Y, P1-068744_E59YE102Y, P1-068748_H31S, P1-068748_H32Y, P1-068748_D57K, P1-068748_D58Y,P1-068748_D100S, P1-068748_H31S_H32Y,P1- 068748_H32YD57K, P1-068748_D57KD58Y, P1-068748_D58YD100S,P1- 068748 H31S D57K, P1-068748_H31SD58Y, P1-068748_H31SD100S, P1-068748_H32YD58Y, P1-068748_H32YD100S, or P1-068748_D57KD100S.
Claim 11 is drawn to an antibody wherein the antibody comprises a VH comprising an amino acid sequence that is at least 90%, 95%, 97%,98% or 99% identical to that of P1-068744_E31S, P1-68744_H50I, P1-68744_E59Y,P1- 068744 E100S, P1-068744_E102Y, P1-068744_E31SH501, P1-068744_H50I E59Y, P1- 068744_E59YE100S, P1-068744_E100SE102Y, P1-068744_E31SE102YP1- 068744_E31SE59Y, P1-068744_E31SE100S, P1-068744_H50IE100S, P1- 068744_H50IE102Y, P1-068744_E59YE102Y, P1-068748_H31S, P1-068748_H32Y, P1- 068748 D57K, P1-068748_D58Y, P1-068748_D100S, P1-068748_H31S_H32Y, P1- 068748_H32YD57K, P1-068748_D57KD58Y, P1-068748_D58YD100S,P1- 068748_H31SD57K, P1-068748_H31SD58Y, P1-068748_H31SD100S,P1- 068748_H32YD58Y, P1-068748_H32YD100S, orP1-068748_D57KD100S; or comprises the amino acid sequence of the VH of P1-068744_E31S, P1-68744_H50I, P1- 68744_E59Y, P1-068744_E100S, P1-068744_E102Y, P1-068744_E31SH50I, P1- 068744_H50IE59Y, P1-068744_E59Y_E100S, P1-068744_E100SE102Y, P1- 068744 E31S E102YP1-068744 E31S E59Y, P1-068744 E31S E100S, P1- 068744_H50I_E100S, P1-068744_H50IE102Y, P1-068744_E59YE102Y, P1- 068748_H31S, P1-068748_H32Y, P1-068748_D57K, P1-068748_D58Y, P1- 068748_D100S, P1-068748_H31SH32Y, P1-068748_H32YD57K, P1- 068748 D57K D58Y, P1-068748_D58YD100S, P1-068748_H31SD57K, P1- 068748_H31SD58Y, P1-068748_H31SD100S, P1-068748_H32YD58Y, P1- 068748_H32Y_D100S, or P1-068748_D57K_D100S, modified by 1, 2, 3, 4, or 5 amino acid substitutions.
Claims 9 and 11 do not disclose a VL regions and there is not enough evidence in the instant disclosure to lead one skilled in the art to know which VLs can be combined with the VH of claims 9 and 11 to obtain the resultant invention of an antibody that specifically binds hVISTA. Furthermore it is unclear which amino acid substitutions in claim 11 will result in a hVISTA antibody.
Claim 13 is drawn to an antibody wherein the antibody comprises a VL comprising an amino acid sequence that is at least 90%, 95%, 97%,98% or 99% identical to that of P1-061015.
The claims encompass a large number of anti-hVISTA antibodies having diverse heavy and light chain CDR amino acid sequences. Following a review of the specification, it appears that Applicant has disclosed numerous anti-hVISTA binding domains, see claims 1 and 2; however in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to encompass multiple anti- hVISTA binding domains having diverse heavy and light chain CDR sequences. 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 hVISTA. 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. Given the substantial antibody structure variation within the genus, the disclosure 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 hVISTA, because the instant specification does not provide structural antibody features that correlate with a functional ability to bind hVISTA. 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 hVISTA 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 hVISTA.
Furthermore while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example in a series of experiments involving a monoclonal antibody to Legionella pneumophilia serotype 1, McCarthy et al. (J. Immunol. Methods, 251(1-2): 137-149, 2001) demonstrated that a single VH CDR3 substitution of tyrosine to serine at position 95 resulted in the total loss of antigen recognition in an ELISA. Lin et al. (African Journal of Biotechnology, 10(79):18294-18302, 2011) teach that a single amino acid substitution in the VL CDR3 of an anti-avian infectious bronchitis virus (IBV) single-chain antibody (ZL.80) may abrogate binding. For example at Figure 3, Lin et al. demonstrate that replacing either the Cys105 or Asp106 residue in the VL CDR3 of ZL.80 with an alanine residue reduces binding to near negative control levels. Lin et al. also teach that some single amino acid substitutions in the VL CDR3 of ZL.80 may significantly improve binding. For example replacing the Val108 residue in the VL CDR3 of ZL.80 with a tyrosine residue results in a 12.9-fold increase in affinity compared to parental ZL.80. Accordingly absent empirical determination, one skilled in the art would be unable to predict or envision which CDR residues of claim 11, for example, could be changed such that the resultant variant CDR residues form an antigen-binding site capable of binding hVISTA. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general, guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of heavy and light chain CDR amino acid sequences, that correlate with the ability to bind hVISTA, and because the disclosed species detailed above are not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to bind hVISTA, 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.”
Claims 18 and 19 recite anti-hVISTA antibodies that bind near the histidine rich region of hVISTA, and absent empirical determination, one skilled in the art would be unable to envision heavy and light chain CDR combinations that result in anti-hVISTA antibodies that bind near the histidine rich region of hVISTA.
Furthermore absent empirical determination, one skilled in the art would be unable to readily envision heavy and light chain CDR combinations that result in anti-hVISTA antibodies that 1) compete with other anti-hVISTA antibodies (claim 20), 2) do not bind to modified hVISTA (claim 22), or 3) possess the functional characteristics recited in claims 23 and 24.
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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) -----9-14, 16-20, 22-25, 27, 41,44-46 are rejected under 35 U.S.C. 102a1 as being anticipated by Johnston et al (WO2018169993; published 09/20/2018).
Johnston et al is drawn towards Vista antibodies at an acidic pH. Johnston et al teach “The isolated antibody of any one of claims 1-122, wherein the antibody competes or cross-competes for binding to h VISTA with one or more antibodies comprising the VH and VL of Pl-061029, Pl-068757, Pl-068759, Pl-068761, Pl-068763, Pl-068765, Pl-068767, Pl-068769, Pl-068771, Pl-068773, Pl-068775, Pl-069059, Pl-069061, Pl-069063, Pl-069065, Pl-069067, Pl-069069, Pl-069071, Pl-069073, Pl-069075, Pl-069077, Pl-069077, Pl-06876l_E55A, Pl-068761_Hl00G, Pl-068761_E56N, Pl-068761_E55A_E56N, Pl-068761_E30D, Pl-068761_E30D ESSA, Pl-068761_E56N_HIO0G,Pl-06876l_E30D HI00G, or Pl-068761_E30D E56N, Pl-068761_El00fF, Pl-068761_E55A_E100fF, Pl-068761_Hl00G_El00fF, Pl-06876l_E30D El00fF, Pl-06876l_E56N_E100fF, Pl-068761_E32Y, Pl-068761_E32Y_E55A, Pl-068761_E32Y_E56N, Pl-068761_E30D E32Y, Pl-068761_E32Y_HIO0G, Pl-068761_E32Y_El00fF, Pl-068767_D52N_D102V, Pl-068767_D52N, Pl-068767_D52N_E55A, Pl-068767_E55A_D102V, Pl-068767_D102V, Pl-068767_E55A, Pl-068767_E30D_D52N, Pl-068767_E30D_D102V, Pl-068767_E30D, Pl-068767 E30D _ESSA, Pl-068767 El00fF D102V, Pl-068767 E55A_El00fF, Pl-068767 D52N_ElO0fF, Pl-068767 El00fF, Pl-068767 E30D ElO0fF, Pl-061015, P1-068736, P 1-068738, P 1-068740, P 1-068742, P 1-068744, P 1-068748, P 1-068750, Pl-068752 or Pl-068754” in claim 123 of the disclosure (Johnston, pg. 302, claim 123). Claim 123 depends from claims 115 and 116 which together disclose an hVISTA antibody comprising a VH of 068744 and 061015 with 100% sequence identity to the elected species 068744_E31S and 061015 (reference SEQ ID NO: 103 and 95, respectively). This meets the limitations of claims 9-14, and 17.
Regarding claim 20 Johnston et al teach measuring the association and the dissociation rates using surface plasmon resonance.
Regarding claim 16, Johnston et al teach the constant region of instant SEQ ID NO:184 (Johnston et al, pg. 252 reference SEQ ID NO: 184).
Regarding claims 18 and 19, Johnston et al teach the antibody binds at histidine rich regions in conditions having a pH of 6.0-6.5 (Johnston et al, pg. 302, claim 122).
Regarding claim 22, Johnston et al teach the antibody of any one of claims 1-123, wherein the antibody does not bind significantly to hVISTA, in which one or more of the following amino acid residues have been mutated: T35, Y37, K38, T39, Y41, R54, T61, F62, Q63, L65, H66, L67, H68, H69, F97, Ll15, Vl17, 1119, Hl21, Hl22, Sl24, El25, Rl27 (Johnston et al, pg. 303, claim 124),
Regarding claim 23, Johnston et al teach the antibody stimulates the binding of hVISTA to human T cells in conditions having a pH of less than pH 7.0 (Johnston et al, pg. 295, claim 66).
Regarding claim 24, Johnston et al teach the antibody can bind to hVISTA at 10, 100, or 1000 fold lower in acidic conditions than neutral or physiological conditions (Johnston et al, pg. 290, claims 3-5).
Regarding claim 25, Johnston et al teach the antibody has an isoelectric point between 6.5 and 6.8 as measured by icIEF (Johnston et al, pg. 303, claim 128).
Regarding claim 27, Johnston et al teach the antibody can be IgG1, IgG2 or IgG4 (Johnston et al pg. 304, claim 135).
Regarding claim 41, Johnston et al teach an isolated nucleic acid encoding the antibody (Johnston et al pg. 305, claim 149).
Regarding claim 44, Johnston et al teach a cell comprising the isolated nucleic acid (Johnston et al, pg. 305, claim 152).
Regarding claim 45, Johnston et al teach a method of preparing the antibody comprising culturing the cell containing the isolated nucleic acid in conditions under which the antibody is expressed (Johnston et al, pg. 305, claim 153).
Regarding claim 46, Johnston et al teach a composition comprising the isolated antibody and a pharmaceutically acceptable carrier (Johnston et al, pg. 305, claim 154).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE K DARPOLOR whose telephone number is (571)272-0115. The examiner can normally be reached 7:30ET-4:30ET.
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/J.K.D./Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642