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
Claims 1-30 are pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-20 and 30, and species E3 ubiquitin ligase, truncated first T3SS E3 ubiquitin ligase polypeptide linked to a truncated second T3SS E3 ubiquitin ligase, and YopM protein transduction domain, the reply filed on 04/13/2026 is acknowledged. However, Applicant does not present any traversal arguments.
The requirement is still deemed proper and is therefore made FINAL.
Claims 3-15, 22-24, and 26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 1-2, 16-21, 25, 27-28, and 30 are examined.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 08/20/2025 and 04/13/2026 are acknowledged and have been considered.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: FIG. 1 on page 10 recite “YopMo”. The specification discloses “YopM” but does not disclose “YopMo”. Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) 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. 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
The disclosure is objected to because of the following informalities: The size of the Sequence Listing disclosed in [0003] should be replaced with “51469 bytes”.
Appropriate correction is required.
Claim Objections
Claim 17 is objected to because of the following informalities: “where in” should be replace with “wherein”. 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.
Claims 1-30 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 claims contain 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.
Claims 1-2 and 29-30 require a construct comprising two or more truncated T3SS bacterial effector polypeptides, wherein each truncated T3SS bacterial effector polypeptide comprises a portion of the corresponding full length T3SS bacterial effector polypeptide, wherein the truncated T3SS bacterial effector polypeptides retain one or more activities of the corresponding full length-T3SS bacterial effector polypeptides, and wherein the T3SS bacterial effector polypeptides are selected from the group consisting of an E3 ubiquitin ligase, a RhoGTPase modulator, a cysteine methyltransferase, a zinc metalloprotease, an acetyltransferase, an O-GlcNac transferase, and an LRR motif binding and sequestration polypeptide. Claims 3-28 require the truncated T3SS bacterial effector polypeptides be linked or fused.
The claims encompass any truncation of the T3SS bacterial effector polypeptides and any fusion or linkage at any amino acid position. The specification has not described any conserved amino acid residues to retain one or more activities of the corresponding full length-T3SS bacterial effector polypeptides. There is no limit to the effects that are claimed and there is no limit to the polypeptides encompassed. The instant specification discloses multiple effector polypeptides (Table 1). These are known in the art. However, there is no guidance in the specification as to which fragments or linked polypeptides of the genus of bacterial effector polypeptides are capable of the required effect. Due to the extremely broad nature of the encompassed polypeptides, there is no description of a representative number of fragments and/or linked fragments which have the required function of retaining one or more activities of the corresponding full length-T3SS bacterial effector polypeptides.
Paz (Molecular Biology Reports 51.1 (2024): 410) reports the proximity of two domains in fusion proteins can result in unfavorable folding, resulting in the loss of activity of one or both catalytic domains. In these cases, adding linker sequences may allow for better conformation, stability, and autonomous actions of each functional domain in a fusion protein (page 410 para. 2). The art does not teach a correlation between structure and function, and one of skill in the art would not have recognized the functionality or the anti-inflammatory activity of the recited structures.
Ruter (US 8,840,901, published 09/23/2014) reports species of truncated YopM from Yersinia with immunomodulatory function (column 46 lines 65-67) and disclosed some truncations abolish this function (column 55 lines 4-10).
Lubos (US-2016/0206713, published 07/21/2016) teaches E3 ubiquitin ligase with N-terminal or C-terminal truncation in the maximal protein-transduction domain ([0117]).
Rauscher (US 2021/0054033 A1) reports fusion of YopM and NLeE (Figure 2)
The prior art disclosure of few species has not established a strong correlation between structure and function, such minimal disclosure in prior art would not lead one skilled in the art to be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species.
The YopM and E3 ubiquitin ligase variants described in Ruter and Lubos references and the fusion YopM-NleE described in Rauscher are not representative of the entire genus when there is substantial variation within the T3SS bacterial effector genus. There may be unpredictability in the functional results obtained from species other than those specifically disclosed in Ruter, Lubos, and Rauscher references. One of skill in the art would not have recognized that the inventor was in possession of the necessary common attributes or features possessed by the species of the genus in view of the species disclosed by Ruter and Lubos. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Therefore, the inventor was not in possession of the full genus of immunomodulatory truncated T3SS bacterial effector genus and of linked truncated T3SS bacterial effector polypeptides retaining one or more activities of the corresponding full-length effector polypeptides.
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 19-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 recites the limitation "the IpaH9.8" in line 1. There is insufficient antecedent basis for this limitation in the claim. Applicant may consider amending the claim to depend from claim 18 to obviate the rejection.
Claims 20-21 which depend from claim 19 do not cure the indefiniteness and are also rejected.
Claim Rejections - 35 USC § 102
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.
Claims 1-2, 27, and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lubos (US 2016/0206713, published 07/21/2016).
Regarding claims 1-2, 27, and 30, Lubos teaches a pharmaceutical composition comprising one or more (i.e., two) of effector proteins or fragment thereof (i.e., truncated) and a carrier ([0263]), and teaches the effectors or their fragments are capable of down-regulating cytokines (i.e., effector polypeptides retain one or more activities of the corresponding full length-T3SS bacterial effector polypeptides) ([0205)]. Lubos teaches the effector protein is selected from the group consisting of SspHl, SspH2, SlrP, IpaHl.4, IpaH2.5, IpaH3, IpaH4.5, IpaH7.8, and IpaH9.8 (i.e., E3 ubiquitin ligase). Lubos teaches the effector proteins are fused to antibodies or other cargo molecules (i.e., the construct comprises a fusion protein) ([0171]).
Claims 1-2, 16-17, 25, 27-28, and 30 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Rauscher (US 2021/0054033 A1).
For clarity of record, US 2021/0054033 is a prior art because it has an earlier effective filing date than instant application (US provisional filed on 01/25/2018 and PCT filed on 01/25/2019) and names another inventor “Frank J. Rauscher” (i.e., a different inventive entity).
Regarding claims 1-2, 16-17, 25, 27-28, and 30, Rauscher teaches a construct comprising a fusion protein comprising an amino acid sequence of a first truncated T3SS bacterial effector polypeptide and an amino acid sequence of a second truncated bacterial effector polypeptide ([0006]). Rauscher teaches that the amino acid sequences of the first truncated bacterial effector polypeptide and the amino acid sequence of the second truncated bacterial effector polypeptide are connected by a linker such as pH sensitive linkers ([0142]). Rauscher teaches fusing two or more different effectors or fragments thereof, and teaches the effectors are NIeC, NleD, NleB, NleH, YopM, YopE, YopH, YopJ, YopP, SspHl, OspG, OspF, IpaH9.8, IpaHl.4, IpaH2.5, IpaH4.5, IpaH7.8 or SlrP ([0006]). Rauscher teaches fusion YopM-NLeE which comprises YopM protein transduction domain (PTD) ([0152], FIG. 2). Rauscher teaches SEQ ID NO: 2 (YopM+YopM PTD) which comprises instant SEQ ID NO:17. Rauscher teaches the constructs can be formulated in pharmaceutical formulation with carrier ([0156]).
Claim Rejections - 35 USC § 103
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.
Claims 1-2, 16-19, 25, 27-28, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Rauscher (US 2021/0054033 A1) in view of Rohde (US 7,892,772, published 02/2011) and as evidenced by Appendix A (sequence alignment, 2026).
Regarding claims 1-2, 16-19, 25, 27-28, and 30, Rauscher teaches a construct comprising a fusion protein comprising an amino acid sequence of a first truncated T3SS bacterial effector polypeptide and an amino acid sequence of a second truncated bacterial effector polypeptide ([0006]). Rauscher teaches that the amino acid sequences of the first truncated bacterial effector polypeptide and the amino acid sequence of the second truncated bacterial effector polypeptide are connected by a linker such as pH sensitive linkers ([0142]). Rauscher teaches fusing two or more different effectors or fragments thereof, and teaches the effectors are NIeC, NleD, NleB, NleH, YopM, YopE, YopH, YopJ, YopP, SspHl, OspG, OspF, IpaH9.8, IpaHl.4, IpaH2.5, IpaH4.5, IpaH7.8 or SlrP ([0006]). Rauscher teaches fusion YopM-NLeE which comprises YopM protein transduction domain (PTD) ([0152], FIG. 2). Rauscher teaches SEQ ID NO: 2 (YopM+YopM PTD) which comprises instant SEQ ID NO:17. Rauscher teaches the constructs can be formulated in pharmaceutical formulation with carrier ([0156]). Rauscher teaches that IpaH9.8 is from Shigella flexneri (Table 2). Rauscher does not teach IpaH9.8 with SEQ ID NO: 11.
However, Rohde teaches IpaH9.8 from Shigella flexneri with 100% sequence identity to instant SEQ ID NO: 11 (See Appendix A pages 1-2 for alignment).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify Rauscher’s composition by substituting fragment of IpaH9.8 with SEQ ID NO: 11 as suggested by Rohde for Rauscher’s IpaH9.8 fragment. One of ordinary skill in the art would be motivated to do so in order to form and anti-inflammatory composition. MPEP 2144.06 II states that it is obvious to substitute equivalents know for the same purpose. Since both Rauscher and Rohde teach IpaH9.8 is from S. flexneri, there is a reasonable expectation of success.
Claims 1-2, 16-17, 19-21, 25, 27-28, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Rauscher (US 2021/0054033 A1) in view of Rohde (US 7,892,772, published 02/2011) and Lubos (US 2016/0206713, published 07/21/2016), and as evidenced by Appendix A (sequence alignment, 2026).
Regarding claims 1-2, 16-17, 19-21, 25, 27-28, and 30, Rauscher teaches a construct comprising a fusion protein comprising an amino acid sequence of a first truncated T3SS bacterial effector polypeptide and an amino acid sequence of a second truncated bacterial effector polypeptide ([0006]). Rauscher teaches that the amino acid sequences of the first truncated bacterial effector polypeptide and the amino acid sequence of the second truncated bacterial effector polypeptide are connected by a linker such as pH sensitive linkers ([0142]). Rauscher teaches fusing two or more different effectors or fragment thereof, and teaches the effectors are NIeC, NleD, NleB, NleH, YopM, YopE, YopH, YopJ, YopP, SspHl, OspG, OspF, IpaH9.8, IpaHl.4, IpaH2.5, IpaH4.5, IpaH7.8 or SlrP ([0006]). Rauscher teaches fusion YopM-NLeE which comprises YopM protein transduction domain (PTD) ([0152], FIG. 2). Rauscher teaches SEQ ID NO: 2 (YopM+YopM PTD) which comprises instant SEQ ID NO:17. Rauscher teaches the constructs can be formulated in pharmaceutical formulation with carrier ([0156]). Rauscher teaches that IpaH4.5 and IpaH9.8 are from Shigella flexneri (Table 2). Rauscher does not teach IpaH9.8 with SEQ ID NO: 11.
However, Rohde teaches IpaH9.8 from Shigella flexneri with 100% sequence identity to instant SEQ ID NO: 11 (See Appendix A pages 1-2 for alignment).
Rauscher and Rohde do not teach IpaH4.5 with SEQ ID NO: 13.
However, Lubos teaches IpaH4.5 from Shigella flexneri with 100% sequence identity to instant SEQ ID NO: 13 (See Appendix A pages 3-4 for alignment) (Figure 20).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify Rauscher’s composition by substituting a fragment of IpaH9.8 with SEQ ID NO: 11 and a fragment of IpaH4.5 with SEQ ID NO: 13 as suggested by Rohde and Lubos for Rauscher’s IpaH4.5 and IpaH9.8 fragments. One of ordinary skill in the art would be motivated to do so in order to form and anti-inflammatory composition. MPEP 2144.06 II states that it is obvious to substitute equivalents know for the same purpose. Since Rauscher, Rohde, and Lubos teach IpaH4.5 and IpaH9.8 from S. flexneri, there is a reasonable expectation of success.
Double Patenting
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 1-2, 16-21, 25, 27-28, and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 6-8 of U.S. Patent No. 12,404,307 in view of Lubos and Rohde.
Regarding instant claims 1-2, 16-21, 25, 27-28, and 30, patent claim 1 recites a composition comprising a set of paired peptides wherein the set of paired peptides is linked to a protein transduction domain, and wherein the set of paired peptides comprises a first bacterial effector polypeptide linked to a second bacterial effector polypeptide, wherein the protein transduction domain is a YopM protein transduction domain, an SspHl protein transduction domain, or an lpaH protein transduction domain wherein the protein transduction domain and the set of paired peptides comprise a fusion protein. Patent claim 2 recites the first bacterial effector polypeptide and second bacterial effector polypeptide are different. Patent claim 3 recites first bacterial effector polypeptide and the second bacterial effector polypeptide are immunomodulatory. Patent claim 6 recites a linker is positioned between the first bacterial effector polypeptide and the second bacterial effector polypeptide. Patent claim 7 recites the protein transduction domain is a YopM protein transduction domain. Patent claim 8 recites the protein transduction domain comprises SEQ ID NO: 5 (i.e., instant SEQ ID NO: 17). Patent claims 1-3 and 6-8 do not recite a pharmaceutical composition with carrier, truncated IpaH9.8, or truncated IpaH4.5.
However, Lubos teaches a pharmaceutical composition comprising one or more (i.e., two) of effector proteins or fragment thereof (i.e., truncated) and a carrier ([0263]), and teaches the effectors or their fragments are capable of down-regulating cytokines (i.e., effector polypeptides retain one or more activities of the corresponding full length-T3SS bacterial effector polypeptides) ([0205)]. Lubos teaches the effector protein is a bacterial effector protein of the selected from the group consisting of SspHl, SspH2, SlrP, IpaHl.4, IpaH2.5, IpaH3, IpaH4.5, IpaH7.8, and IpaH9.8 (i.e., E3 ubiquitin ligase). Lubos teaches IpaH4.5 is 100% identical to instant SEQ ID NO: 13 (See Appendix A pages 3-4 for alignment). Lubos teaches the effector is fused to cleavable linker ([0182]).
Lubos does not teach IpaH9.8 with SEQ ID NO: 11.
However, Rohde teaches IpaH9.8 from Shigella flexneri with 100% sequence identity to instant SEQ ID NO: 11 (See Appendix A pages 1-2 for alignment).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition recited in patent claims 1-3 and 6-8 by fusing truncated IpaH9.8 and IpaH4.5 with SEQ ID NO: 11 and 13 respectively, as suggested by Lubos and Rohde. One of ordinary skill in the art would be motivated to do so in order to form and anti-inflammatory composition. MPEP 2144.06 II states that it is obvious to substitute equivalents know for the same purpose.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY A CRUM whose telephone number is (571)272-1661. The examiner can normally be reached M-F 8:00-5:00 CT with alternate Fridays off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LOUISE W HUMPHREY can be reached at 571-272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARY A CRUM/Examiner, Art Unit 1657
/THANE UNDERDAHL/Primary Examiner, Art Unit 1699
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