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
Claims 1-8, 11-15, and 18-20 are currently pending. Claims 9-11 and 16-17 are cancelled.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/27/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/27/2026 has been entered.
WITHDRAWN REJECTIONS
Previous 35 USC § 112(a) rejections of the pending claims have been withdrawn following claim amendments. New rejections are set forth below.
NEW REJECTION NECESSITATED BY AMENDMENTS
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.
Claims 1-8, 11-15, and 18-20 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.
Regarding claim 1: A composition, wherein the composition comprises:
a vaccinia virus, wherein the vaccinia virus comprises an exogenous nucleic acid that comprises a sequence that codes for an IgE or domain thereof fused to
a variant High Mobility Group Box 1 (HMGB 1) protein,
wherein the variant HMGB 1 protein comprises at least one variant nuclear localization signal (NLS),
wherein the at least one variant NLS provides for increased cytoplasmic re- location of the variant HMGB 1 compared to a wild type HMGB 1,
wherein the variant NLS comprises mutations at one or more of amino acids 35, 42, and 181 according to sequence numbering of SEQ ID NO: 16,
wherein the fused protein comprises an amino acid sequence with at least 90% identity to an amino acid sequence described by SEQ ID NO: 24, and
wherein expression of the variant HMGB 1 enhances tumor-specific replication of the vaccinia virus compared to an otherwise identical vaccinia virus that lacks the exogenous nucleic acid coding for the variant HMGB 1.
It is initially pointed out that this claimed composition encompasses all polypeptides comprising >90% identity to SEQ ID NO: 24 (233 amino acids).
Applicant’s specification does not provide support for all polypeptides comprising 90% identity to SEQ ID NO: 24. The specification as filed does not provide sufficient evidence that Applicants were in possession of the full scope of the claimed invention at the time of filing of the instant invention. As such, >90% identity to a 233 amino acid polypeptide, encompasses
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polypeptide molecules, if only substitution mutations were considered. It is noted that the variant language as encompassed by the claim also covers insertions and deletions. This amounts to enormous number of polypeptides which do not have support in the specification. The specification also does not provide any guidance on how or where the amino acids could be changed that would produce the claimed functional limitations – i.e. enhances tumor-specific replication of the vaccinia virus or increased cytoplasmic re- location of the variant HMGB1. The language of the claim requires a mutation at positions 35, 42 and 181, but does not limit mutations at other positions. Nor does the specification provide any guidance regarding how to change the amino acids at the claimed 35, 42 and 181 positions. It is clear that the vector of the invention was restricted to SEQ ID NOs: 24-25. For example, see instant specification at [0070].
Thus, Applicants were not in possession of the full scope of the claimed invention at the time of filing of the instant invention. It is submitted that the specification does not provide structural features common to substantially all members of the claimed genus. The disclosure of limited number of specific variants does not constitute possession of entire genus as encompassed by the claim.
Claims 1-8, 11-15, and 18-20 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 enablement requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant's specification is found enabling for vaccinia virus encoding HMGB1 variants comprising SEQ ID NOs: 14, 15, 17, 19, 13, 24 or 25, fused to IgE.
Applicant's specification is not found to be enabling for all HMGB1 polypeptides comprising variant NLS comprising mutations at one or more of amino acids 35, 42, and 181 according to sequence numbering of SEQ ID NO: 16, wherein the fused protein comprises an amino acid sequence with at least 90% identity to an amino acid sequence described by SEQ ID NO: 24 that have the functional limitations of enhancing tumor-specific replication of the vaccinia virus compared to an otherwise identical vaccinia virus that lacks the exogenous nucleic acid coding for the variant HMGB1 and has increased cytoplasmic re-location compared to a wild type HMGB1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the method of the invention commensurate in scope with the current claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Applicants' claims are directed to all HMGB1 variants that are 90% identical to SEQ ID NO: 24 and also comprise mutations at one or more of amino acids 35, 42, and 181 according to sequence numbering of SEQ ID NO: 16. The breadth of the claims includes more than
1
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polypeptides, and have the functional limitations of enhancing tumor-specific replication of the vaccinia virus compared to an otherwise identical vaccinia virus that lacks the exogenous nucleic acid coding for the variant HMGB1 and has increased cytoplasmic re-location compared to a wild type HMGB1.
The specification provides support for TK deleted vaccinia virus encoding an IgE-fused HMGB1 mutant with NLS mutations. The specification provides support for enhanced tumor selective replication and therapeutic activity of vaccinia expressing HMGB1mut by analyzing in vivo efficacy, immune analysis, replication studies in tumors, synergy with chemotherapeutics, and combination with hyaluronidase. The specification showed that AAV encoding HMGB1mut with or without PH20 reduced tumor burden and showed synergy with chemotherapy in murine models. It was also shown that HSV expressing HMGB1mut demonstrated enhanced anti-tumor effects and chemotherapy synergy. Recombinant AAV, VSV, NDV SVV, Coxsackievirus, Reovirus expressing HMGB1 showed reduced tumor burden.
At the time the invention was made it was known that HMGB1’s cellular localization is dynamically controlled by complex regulatory factors such as phosphorylation and even simultaneous mutation of residues in the NLSs changes nuclear import/export in ways that were not simple or predictable. For example, Youn taught that “serine residues of either or both NLSs of HMGB1 to glutamic acid to simulate a phosphorylated state and examined the binding of HMGB1 to karyopherin-α1, which was identified as the nuclear import protein for HMGB1 in this study. Substitution to glutamic acid in either NLSs decreased the binding with karyopherin-α1 by ~50%; however, substitution of both NLSs showed no binding, and HMGB1 was relocated to the cytoplasm and subsequently secreted.” (See Youn Abstract; See PTO-892 02/04/2025). It was also known that HMGB1 acetylation and shuttling depended on multiple modifications and interacting proteins, not on simple primary sequence substitution alone. For example, __ taught “Again, when lysines 181, 182, 183 of the HMGB1–GFP fusion were changed into alanines (KKK→AAA-2), the fusion protein remained nuclear. Double mutants of HMGB1–GFP where both lysine clusters were changed to alanines or glutamines were clearly present in the cytoplasm (2×KKK→AAA and 2×KKK→QQQ), whereas the change of lysines into arginines did not affect the nuclear localization of the protein (Figure 3B, 2×KKK→RRR). Remarkably, however, even the double HMGB1 mutants were present in higher amount in the nucleus than in the cytoplasm. Apparently, HMGB1 is endowed with several regions that can contribute to nuclear localization, albeit not as isolated peptides but only in the context of the whole protein, as was previously shown for HMGB2” (See Bonaldi et al; p. 5555; col. 1, last para; Figure 3; See PTO-892).
It was also known at the time of filing that molecular bases governing viral replication and host interactions was incompletely understood. For example, Kaufman taught that “[r]ecent evidence has suggested that the kinetics of immune-mediated responses may be much slower when compared to therapeutic agents that directly kill tumour cells. Activation of the immune system results in an indirect method of tumour cell killing, which requires the priming and expansion of immune effector cells, most notably CD8+ cytotoxic T cells, and time for such cells to undergo homeostatic expansion, trafficking to sites of tumour growth, lytic destruction of cancer cells and inflammatory clearance of the necrotic tumour” (See Kaufman; p. 658, col. 1 last para to col. 2 first para; See PTO-892). Therefore, there was a recognized level of unpredictability with regards to HMGB1 localization as well as viral replication.
Due to the lack of teachings in the art regarding which mutations in HMGB1 would reliably alter nuclear localization and cytoplasmic localization, and the recognized unpredictability in the area of tumor selective viral replication and functional consequences of modified HMGB1 in different viral platforms, a large amount of guidance and teachings would be necessary in order to be enabling for methods of such. A person of ordinary skill in the art would sill have to create the encompassed variants, test localization, test viral replication across an astronomically large genus.
Guidance and teachings provided by Applicants in the instant specification is limited to disclosure that specific variants produced functional limitations in the claim. It is acknowledged that the Office does not require the presence of working examples to be present in the disclosure of the invention (see MPEP §2164.02). However, in light of the state of the art, discussed above, which recognizes a high level of unpredictability in the field of HMGB1 protein structure-function relationship and tumor specific viral replication, the Office would require appropriate disclosure to support the claimed composition. 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). Thus, due to the high level of unpredictability in the art, the current specification would have to provide greater amounts of teachings and guidance directed to methods of carrying out the claimed invention.
Therefore, due to the sum of all the aforementioned factors, one of ordinary skill in the art, at the time the invention was made, would not readily be able to arrive at the claimed compositions without undue experimentation. Accordingly, claims 1-8, 11-15, and 18-20 are deemed properly rejected.
Conclusion
No claim is allowed.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633