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
Claim Status
Applicant’s amendment filed June 24, 2026 has been received and entered.
Claims 1-5, 7-12, and 14-16 have been amended.
Claim 6 was previously canceled.
Claims 17-18 have been added.
Claims 1-5 and 7-18 are pending and under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted 6/24/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections - Withdrawn
The previous objections to claims 2-5, 7-8, 10-12, and 16 for minor informalities have been withdrawn in view of Applicant’s claim amendments.
Claim Rejections - 35 USC § 112(b) - Withdrawn
The previous rejection of claims 1-5 and 7-16 are rejected under 35 U.S.C. 112(b) as being indefinite has been withdrawn in view of Applicant’s claim amendments which now recite the instantly claimed bacteria is a virulence attenuated bacterial strain.
The previous rejection of claims 1-5 and 7-16 under 35 U.S.C. 112(b) as being indefinite has been withdrawn in view of Applicant’s claim amendments deleting the “optional” phrase from the claims.
The previous rejection of claims 3 and 14 under 35 U.S.C. 112(b) as being indefinite has been withdrawn in view of Applicant’s claim amendments deleting reference to other CARD domain containing proteins.
The previous rejection of claims 3 and 14 under 35 U.S.C. 112(b) as being indefinite has been withdrawn in view of Applicant’s claim amendments deleting the term “such as” from the claims.
The previous rejection of claims 3-4 and 14-15 under 35 U.S.C. 112(b) as being indefinite has been withdrawn in view of Applicant’s claim amendments deleting the terms “RIG-I-like” and “DisA-like” from the claims.
Claim Rejections - 35 USC § 112(a) – Written Description – Updated/Maintained
The previous rejection of claims 1-2, 5, 7-10, 13, and 16 under 35 U.S.C. 112(a), as failing to comply with the written description requirement has been updated after consideration of Applicant’s arguments.
Claims 1-2, 7-9, and 13 are drawn to a recombinant Gram-negative bacterial strain that encodes a heterologous protein.
Claims 5, 10, and 16 recite the Gram-negative bacteria is a Yersinia strain.
The claims were previously rejected because the claims encompass a large genus of undefined heterologous proteins with no recited structure or function. Given the infinite number of possible heterologous proteins, the skilled artisan would not have been in possession of the vast repertoire of heterologous proteins encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of heterologous proteins, including those that are involved with the induction or regulation of an IFN response, with the claimed specificity and functional attributes, broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Applicant’s Arguments
Applicant argues beginning on page 8 of the reply received June 24, 2026 that the Yersinia strain used in the present invention is capable of secreting a representative number of species of heterologous proteins. Applicant further cite U.S. Patent Nos. 10,889,823 and 11,518,789, which disclose numerous proteins that are secreted by the Yersinia strain used in the present invention.
Response to Arguments
Applicant’s arguments have been fully considered and are deemed persuasive in regard to instant claims 5, 10, and 16. Specifically, claims 5, 10, and 16 recite the Gram-negative bacteria is a Yersinia sp., which have been shown to secrete a variety of heterologous proteins.
However, claims 1-2, 7-9, and 13 are drawn to Gram-negative bacteria broadly.
Claims 2 and 13 recite the heterologous protein is involved in in induction or regulation of an interferon (IFN) response.
The claims encompass a large genus of undefined proteins with no recited structure or function. The state of the art is such that generating recombinant bacteria to produce heterologous proteins is an extremely complex process and requires a deep understanding of microbial genetics and bacterial delivery systems. In regard to Gram-negative bacteria in particular, Burdette et al. (2018; cited IDS 9/11/2024) teaches they are favored as bacterial hosts for protein production, as they can express a broad range of heterologous proteins. However, intracellular overexpression of recombinant proteins in bacteria often leads to the formation of insoluble aggregates, or inclusion bodies [pg. 2, col. 1]. Burdette further teaches that selecting a strain of Gram-negative bacteria is dependent on the type of secretion system and compatibility with the desired protein product, as folding kinetics, folding complexity, and protein size can play a role in secretion efficiency. Therefore, secretion efficiency is highly dependent on the heterologous protein, yet no concrete design rules exist [pg. 3-4].
Regarding heterologous proteins involved in IFN regulation and/or induction, Negishi et al. (2018) teaches the regulation of an IFN response is a complex process that is still not fully understood. Negishi teaches there are three types of IFNs which are regulated by IFN regulatory factor (IRF) transcription factors which has nine family members, which each comprise a multitude of different proteins that are involved in the regulation of IFN [pg. 2-3]. A recent publication (Wang et al., 2024) illustrates the complexity of the major proteins directly involved in regulation of an IFN response [Fig. 3].
The specification discloses "a heterologous protein or a fragment thereof” includes naturally occurring and engineered proteins or a fragments thereof which do not belong to the proteome of the Gram-negative bacterial strain. Particularly preferably, the heterologous protein or a fragment thereof is selected from the group consisting of proteins involved in induction or regulation of an interferon (IFN) response, proteins involved in apoptosis or apoptosis regulation, cell cycle regulators, ankyrin repeat proteins, reporter proteins, small GTPases, GPCR related proteins, nanobody fusion constructs, bacterial T3SS effectors, bacterial T4SS effectors and viral proteins [pg. 34-35]. Multiple proteins are listed in the specification, however, only examples of two heterologous proteins (RIG-I and cGAS) that were delivered by the Gram-negative Y. enterocolitica strain are provided [pg. 38].
The instant application has not provided a sufficient description showing possession of the
necessary 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 genus of heterologous proteins encompassing various structures, delivery mechanisms, and functions.
Given the infinite number of possible heterologous proteins, the skilled artisan would not have been in possession of the vast repertoire of heterologous proteins encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of heterologous proteins, including those that are involved with the induction or regulation of an IFN response, with the claimed specificity and functional attributes, broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
The Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent
specification to “describe the claimed invention so that one skilled in the art can recognize what is
claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s
“disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter
purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir.
1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must 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." (See Vas-Cath, p. 1117). The specification does not "clearly allow persons of ordinary skill in
the art to recognize that [he or she] invented what is claimed." (See Vas-Cath, p. 1116).
Also, it is noted that the Court has held that the disclosure of screening assays and general
classes of compounds was not adequate to describe compounds having the desired activity: without
disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of
Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in
“possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support
need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein
v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —
i.e., what the written description and knowledge in the art would lead one to speculate as to
modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also
ensures that when a patent claims a genus by function, the specification recites sufficient materials to
accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Given the claimed broadly class of heterologous proteins, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Therefore, there is insufficient written description for the genus of heterologous proteins in method of treatment of a subject with cancer encompassed by the claimed invention to provide sufficient structure for the heterologous proteins claimed at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Accordingly, the rejection of claims 1-2, 7-9, and 13 as failing to comply with the written description requirement is maintained.
Claim Rejections - 35 USC § 112(a) – Enablement- Withdrawn
The previous rejection of claims 7-8 and 13-16 under 35 U.S.C. 112(a) for failing to comply with the enablement requirement has been withdrawn in view of Applicant’s deletion the term “prevention of cancer”.
Claim Rejections - 35 USC § 103 - Withdrawn
The previous rejection of claims 1-5 and 7-16 under 35 U.S.C. 103 as being unpatentable over Ittig et al. (WO 2018/115140; cited IDS 6/3/2024) (“Ittig”), in view of Stevenson et al. (WO 2019/141998) (“Stevenson”) as evidenced by National Cancer Institute (www.cancer.gov/publications/dictionaries/ cancer-drug/def/ezabenlimab; Accessed 18 March 2026) is withdrawn in view of Applicant’s arguments.
Applicant’s Arguments
Applicant argues beginning on page 8 of the reply received June 24, 2026 that Ittig teaches a Y. enterocolitica strain to express and secrete cGAs or RIG-1 in vitro, but does not teach or suggest combining with an immune checkpoint inhibitor. Further, although Stevenson teaches ezabenlimab in combination with an Enterococcus strain, the results show that there was minimal difference between the Enterococcus gallinarum strain (MRX518) combined with ezabenlimab compared to treatment with an inhibitor alone and the bacterial composition alone.
Response to Arguments
Applicant’s arguments have been fully considered and are deemed persuasive. The data presented by Stevenson shows that a combination therapy comprising an Enterococcus gallinarum strain (MRX518) and an immune checkpoint inhibitor is not more effective than either treatment as a monotherapy which does not provide for a reasonable expectation of success in combining the protocols of Ittig and Stevenson as combination treatments.
Nonstatutory Double Patenting - Withdrawn
The previous rejections of the instant claims on the ground of nonstatutory double patenting as being unpatentable over one or more claims of US Patent Nos. 12,358,955, 11,518,789, and 11,702,663, and the provisional rejection over Application No. 19/232,635 have been withdrawn because the patented claims or copending claims do no teach or suggest a virulence attenuated Gram-negative bacterial strain administered in combination with ezabenlimab or any other immune checkpoint inhibitor as recited in the instant claims.
Nonstatutory Double Patenting – Maintained/Updated
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5 and 7-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 14 12-15 of copending Application No 18/551,502.
Copending claim 1 is drawn to a pharmaceutical combination comprising a polynucleotide molecule comprising a nucleotide sequence encoding a heterologous protein or fragment thereof, and immune checkpoint modulator (ICM), and one or more pharmaceutically acceptable diluents or excipients. Copending claim 2 recites the heterologous protein regulates IFN. Copending claims 3-5 recite examples of heterologous proteins. Copending claims 6-8 recite the ICM is an anti-PD-1 antibody. Copending claim 12 recites the bacteria is a Yersinia strain. Claims 13-14 recite the combination is for use in a method for the prevention, treatment, or delay of cancer. Claim 15 is drawn to a kit comprising the pharmaceutical combination.
The copending claims differ from the instant invention in that although the immune checkpoint inhibitor is an anti-PD-1 antibody, it does not recite the antibody is ezabenlimab.
However, the instant specification defines ezabenlimab as an anti-PD-1 antibody [pg. 82, lines 21-22]. Accordingly, the instant invention is a modification of the copending claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571)270-0730. The examiner can normally be reached Monday through Friday.
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/MAUREEN VARINA DRISCOLL/
Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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