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 the Claims
1. Claims 1-31 are the original claims filed 9/29/2023. IN the preliminary amendment of 9/29/2023, claims 1-31 are canceled and new claims 32-51 are added. Claims 32-51 are all the claims.
Election/Restrictions
2. Applicant’s election without traverse of Group I (Claims 31-46) in the reply filed on 5/26/2026 is acknowledged. Applicant’s election without traverse of species (prophylactic) in the reply filed on 5/26/2026 is acknowledged.
3. Claims 47-51 and the species therapeutic are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/26/2026.
4. Claims 32-46 are the claims under examination.
Priority
5. USAN 18/284,894, filed 09/29/2023, is a National Stage entry of PCT/US2022/ 022557, International Filing Date: 03/30/2022, PCT/US2022/ 022557 Claims Priority from Provisional Application 63/168,077, filed 03/30/2021.
Information Disclosure Statement
6. As of 7/8/2026, a total of two (2) IDS are filed: 10/16/2023; and 7/1/2025. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Drawings
7. The drawings are objected to because: Fig 3C is out of sequence from Fig 3A and 3B. Figure 3C is on the same page as Figure 1; and Figure 5 depicts two panels (unlabeled) in landscape presentation whilst the corresponding figure legend describes the panels (unlabeled) as upper and lower.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
8. The disclosure is objected to because of the following informalities:
a) The use of the term Tris, ATCC, Octet, GelCode, Superdex, lipofectamine, BriteLite, SpectraMAx, Expi293, OPti-MEM, nanoDSF, ISAC, YOLO, Sepharose, Expifectamine, QuickChange, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) The specification is improper for teaching peptides > 4 amino acids in length (i.e., RRRRRR) that are required to be identified by a sequence identifier pursuant to 37 CFR 1.821-1.825.
Appropriate correction is required.
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.
Written Description
9. Claims 32-33, 35-41 and 43-46 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 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.
Claim interpretation
Claims 32-33 and 35-40 drawn to a genus of non-natural trimers comprising clade C human HIV-1 1086.c ENV stabilized by a disulfide SOSIP mutation with a mutation/substitution of I559P in claims 32 and 35. The trimer is functionalized to contain at least one of a broadly neutralizing epitope and an anti-V1/V2 antibody-inducing epitope.
Claims 41 and 43-44 drawn to immunogenic composition for eliciting an immune reaction in cells against clade C human immunodeficiency virus type-1 (HIV-1) comprising a genus of non-natural trimers comprising clade C human HIV-1 1086.c ENV stabilized by a disulfide SOSIP mutation with a mutation/substitution of I559P, at least one adjuvant and a pharmaceutically acceptable carrier in claim 41.
Claim 45 drawn to a prophylactic vaccine against HIV-1 comprising a genus of non-natural trimers comprising clade C human HIV-1 1086.c ENV stabilized by a disulfide SOSIP mutation with a mutation/substitution of I559P, and at least one of a pharmaceutically acceptable carrier, an adjuvant, and a different HIV-1 envelope (ENV) trimer from clade C or from a clade type other than clade C.
Claim 46 drawn to a kit comprising a prophylactic vaccine against HIV-1 comprising a genus of non-natural trimers comprising clade C human HIV-1 1086.c ENV stabilized by a disulfide SOSIP mutation with a mutation/substitution of I559P, and at least one of a pharmaceutically acceptable carrier, an adjuvant, and a different HIV-1 envelope (ENV) trimer from clade C or from a clade type other than clade C or the individual elements.
“broadly neutralizing epitope”: the specification does not describe an example nor does it define the meaning of the phrase for the 1086.c species of HIV-1 ENV.
“epitope” (anti-V1/V2 antibody inducing): the specification does not describe an example nor does it define the meaning of the phrase for the 1086.c species of HIV-1 ENV.
“immunogenic”: the specification identifies examples of what regions are immunogenic at
[0056] The antigenicity of the 1086.c SOSIP trimer was next assessed by conducting binding assessments of bnAbs to the trimer. The bnAb binding profile of the 1086.c SOSIP trimer was compared with the BG505 SOSIP.664 using an extensive panel of 19 bnAbs including antibodies recognizing well-characterized immunogenic portions of the ENV protein such as V2 apex, CD4 binding site (CD4 bs), V3 loop/glycan patch, and the gp120/gp41 interface. The affinity of the RV144-related functional CH58 mAb to both SOSIP trimers was also compared.
“immune reaction”: the specification does not describe an example nor does it define the meaning of the phrase for the 1086.c species of HIV-1 ENV.
Scope of the Claims
The claims encompass a HIV-1 1086.c ENV protein and/or any fragment thereof in a trimeric formation so long as the trimer comprises a SOSIP mutation, a I559P mutation, at least one of a broadly neutralizing epitope and an anti-V1/V2 antibody-inducing epitope, is immunogenic for eliciting any immune reaction in any kind of cells, and is a prophylactic vaccine. Because applicant seeks patent protection for all such trimers, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The 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’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
All the claims require any part of or all of a clade C human HIV-1 1086.c ENV protein comprising within the trimer made of the same, a SOSIP and I559P mutation. The claims do not define the location of the SOSIP mutation nor is the location of the I559P mutation appreciable from the data shown in the application for the protein sequences corresponding to the trimer. For example, SEQ ID NO: 2 (Clade C HIV-1 1086.c ENV SOSIP trimer protein sequence without a signal sequence) consists of 627 amino acids but does not disclose an I(Ile)559 residue in the sequence for the sequence listing:
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.
For example, SEQ ID NO: 3 (Clade C HIV-1 1086.c ENV SOSIP trimer protein sequence with a signal sequence) consists of 662 amino acids but does not disclose an I(Ile)559 residue in the sequence for the sequence listing:
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Claims 33 and 36 require the trimer complex comprise at least one of a broadly neutralizing epitope and an anti-V1/V2 antibody inducing epitope. The structure(s) much less the amino acid positions in the trimer complex are not described in any claims of the invention much less in the specification.
Claims that recite generation an immune response do not identify the cells responsive to the trimer complex much less whether those cells are protective in achieving the prophylactic endpoint.
Summary of species disclosed in the specification
Applicant’s specification fully discloses a single example of a trimer consisting of the nucleotide sequence of SEQ ID NO:1 (1086.c SOSIP) or the protein sequence of SEQ ID NO: 2 or 3. Those data for the 1086.c SOSIP trimer protein are compared to BG505 SOSIP.664 and other anti-HIV-1 specific antibodies in Fig 6 and 7:
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Are the disclosed species representative of the claimed genus?
It is asserted that the single disclosed species is not representative of the claimed genus because the claims encompass a HIV-1 1086.c ENV protein and/or any fragment thereof in a trimeric formation so long as the trimer comprises a SOSIP mutation, a I559P mutation, at least one of a broadly neutralizing epitope and an anti-V1/V2 antibody-inducing epitope, is immunogenic for eliciting any immune reaction in any kind of cells, and is a prophylactic vaccine.
None of the data demonstrate the effect on immune cells in vitro or in vivo much less the prevention of clade C human HIV-1 in a living subject.
“Several studies have shown that the presence of broadly neutralizing Ab epitopes on Env immunogens including trimers does not translate to immunogenicity in that these Env immunogens often do not elicit broadly neutralizing responses at a re sonable titer in vaccinated animals” and there is “the lack of direct correlation between HIV Env antigenicity and immunogenicity,…” (p. 768, Col., 2) Bontempo (PTO 892).
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional variants. One of ordinary skill in the art could not reasonably conclude that any trimer of the instant claim scope performed and/or possessed a structure/function correlation with the protein encoded by SEQ ID NO: 1 based on the limited amount of description or working examples in the application.
MPEP 2163 II(A)(3)(a)(i):
Whether the specification shows that the inventor was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the inventor was in possession of the claimed species is sufficient. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. The description needed to satisfy the requirements of 35 U.S.C. 112 “varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence.”
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the trimer genus for reliably assigning different structural elements based on sequence data for a single trimer clone, which would support the premise that the inventors possessed the full scope of the claimed invention.
Rejections Maintained
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.
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.
10. The rejection of Claim(s) 32-33, 35-39, 41 and 43-46 under 35 U.S.C. 103 as being unpatentable over Duke (WO 2020/068779; 02 April 2020 (02.04.2020); IDS 10/16/2023) in view of HEALTH AND HUMAN SERVICES (HHS) ((US 2019/0389915 A1; December 2019 (26.12.2019); IDS 10/16/2023) is maintained.
Applicants did not respond to the original grounds for rejection set forth in the Office Action of 3/26/2026 herein as follows:
Duke teaches a trimer comprising a non-naturally occurring Clade C human HIV-1 1086.c envelope (ENV) trimer stabilized by a SOSIP mutation of instant claims 32, 35, 41, 45 and 46:
[007] In certain embodiments the envelope is any of the forms of HIV- 1 envelope. In certain embodiments the envelope is gpl20, gpl40, gpl45 (i.e. with a transmembrane domain), or gpl50. In certain embodiments, gpl40 is designed to form a stable trimer. See WO/2017/15180, e.g Table 1, Figures 22-24, Example 9, and paragraphs [0501] et seq. for non-limiting examples of sequences of stable trimer designs, which contents are incorporated by reference in their entirety. In certain embodiments envelope protomers form a trimer which is not a SOSIP timer. In certain embodiments the trimer is a SOSIP based trimer wherein each protomer comprises additional modifications. In certain embodiments, envelope trimers are recombinantly produced.
[0013] In certain embodiments, the compound is gpl20 HIV-l envelope 1086. C.
[0055] Figures 10A-10E show enhancement of vaccine-elicited antibodies in mice immunized with a nanofiber-conjugated gpl20 vaccine. (Figure 10A) Higher magnitude of 1086. c gpl20-specific antibodies in mice immunized with 50pg Ql l nanofiber-conjugated gpl20 (gpl20-Ql l) than in mice immunized with gpl20 alone.
Duke teaches pharmaceutical compositions as immunogenic compositions in claims 11 as for instant claims 35 and 41.
Duke teaches bnAb epitopes on trimers at [00115, 00137, 00144] of instant claims 33 and 36.
Duke teaches an HIV-l envelop trimer is CH505 T/F at [0014] of instant claims 37 and 43.
Duke teaches an HIV-1 envelope trimer BG505 SOSIP at [0049, 0128] of instant clams 38 and 44.
Duke teaches nucleic acids at [0098] of instant claim 39.
Duke teaches prevention of infection at [00157] of instant claim 45.
As regards claims 32, 35, 41, 45 and 46, HHS teaches stabilized HIV-1 Env ectodomain trimers (Abstract) comprising a non-naturally occurring Clade C human HIV-1 envelope (ENV) trimer stabilized by a SOSIP mutation with an isoleucine substitution for proline at residue 559.
[0245] In some embodiments a recombinant HIV-1 Env ectodomain included in the disclosed trimers includes a gp120 polypeptide and a gp41 ectodomain including amino acid sequences at least 75% (for example at least 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to a corresponding native HIV-1 gp120 or gp41 ectodomain polypeptide sequence (e.g., a native gp120 or gp41 ectodomain protein sequence from a clade A, B, C, D, F, G, H, J or K HIV-1 Env protein), such a native HIV-1 sequence available in the HIV Sequence Database (hiv-web.lanl.gov/content/hiv-db/mainpage.html) or a native HIV-1 Env polypeptide sequence set forth in Table 5, and include the one or more amino acid substitutions that stabilize the protein in the prefusion mature closed conformation.
[0009] In some embodiments, the recombinant HIV-1 Env ectodomain can be stabilized in the prefusion mature closed conformation by a non-natural disulfide bond between cysteine substitutions at positions 201 and 433. In additional embodiments, the recombinant HIV-1 Env ectodomain can be stabilized in the prefusion mature closed conformation by a non-natural disulfide bond between cysteine substitutions at positions 201 and 433, a non-natural disulfide bond between cysteine substitutions at positions 501 and 605, and a proline substitution at position 559.
[0035] FIGS. 19A-19B are a set of ribbon diagrams showing modeling of gp41 residues 548-568. At low contour, suggestive density is observed that might correspond to the connection between α6 and α7 helices. To investigate the degree to which a model for this region might be defined, two different models for this region were built and refined, as shown in FIG. 19A, with electron density shown for 2F.sub.0-F.sub.c density at 1σ contour. The location of the I/P mutation at 559 is indicated. FIG. 19B, Superimposed models shown in perpendicular orientations.
[0030] FIG. 15 is a table listing the modeling parameters for gp120 and gp41 rearrangements. To provide reference frames for the various prefusion conformational states, we extracted Env component of SOSIP bound by VRC-PG04 (Lyumkis, et al. Science 342, 1484-1490 (2013)) and by VRC03 (Bartesaghi, et al. Nature structural & molecular biology 20, 1352-1357 (2013)) and the resultant maps with the CD4-bound conformation trimeric BAL (Tran, et al. PLoS pathogens 8, e1002797 (2012)). Once maps were aligned, gp120 and gp41 models were fit to each of the maps as defined in the table in black text after “gp120” and “gp41”. In addition to rigid-body fits of crystal structures, specific regions of gp120 and gp41 were modeled and are defined in the table in red text after different portions of gp120 and gp41 relative to the prefusion mature closed conformation.
Exterior HIV Envs are in a trimeric configuration on the virion surface. HIV Env native-like trimer immunogens are better at binding and eliciting broadly neutralizing Abs than nontrimer and monomeric gp120 Env immunogens. Multivalency is critical in activating B-cells because of BCR cross-linking HIV vaccines. Both references teach overlapping Env trimer-based structure for immunization strategies; that a supramolecular form of the SOSIP trimer comprising stabilizing residue substitutions, I/P 559, that can improve antibody titers and durability. Accordingly, where the references alone and combined provide proof-of-principle examples for constructs reading on and encompassing the instant claimed trimer, the POSA could predict and be reasonably assured of success in making and using the invention.
The rejection is maintained.
11. Claim(s) 40 and is/are rejected under 35 U.S.C. 103 as being unpatentable over Duke (WO 2020/068779; 02 April 2020 (02.04.2020); IDS 10/16/2023) in view of HEALTH AND HUMAN SERVICES (HHS) ((US 2019/0389915 A1; December 2019 (26.12.2019); IDS 10/16/2023) as applied to claim 32 above, and further in view of Amara (US-20220401546-A)) and Sahoo (Journal of the International AIDS Society, (2020) Vol. 23, No. SUPPL 4. Abstract Number: OAA0305. Meeting Info: 23rd International AIDS Conference. Virtual. 06 Jul 2020-10 Jul 2020).
Sahoo teaches about 50% of global HIV-1 infections are due to clade C viruses and there is a great need for the development of stabilized natively like trimeric clade C gp140 protein immunogen for inducing neutralizing antibodies by vaccination. To develop a stable trimer, we adopted recent structure guided strategies to design SOSIP and other structure forms of the protein to improve the stability of the ENV for C.1086.
Amara teaches at [0074] The C.1086 based gp140 trimer would be of interest because unstable C.1086 gp140 protein does not induce autologous neutralizing antibodies. Amara teaches SOSIP and mutation stabilizing residues at [0069]. Amara teaches the expression of HIV-1 clade C trimers from Poxvirus vectors including adenoviral or MVA at [0059].
Exterior HIV Envs are in a trimeric configuration on the virion surface. HIV Env native-like trimer immunogens are better at binding and eliciting broadly neutralizing Abs than nontrimer and monomeric gp120 Env immunogens. Multivalency is critical in activating B-cells because of BCR cross-linking HIV vaccines. All four references teach overlapping Env trimer-based structure for immunization strategies; that a supramolecular form of the SOSIP trimer comprising stabilizing residue substitutions, I/P 559, that can improve antibody titers and durability. All four references teach expression of the trimer from a vector-based system whilst Amara promotes the use of adenoviral or MVA vectors to accommodate the design of the trimer complex. Accordingly, where the references alone and combined provide proof-of-principle examples for constructs reading on and encompassing the instant claimed trimer, the POSA could predict and be reasonably assured of success in making and using the invention.
Conclusion
12. No claims are allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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