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 47-48, 64, and 66-68 are canceled. Claims 1-46, 49-63, 65, and 69-88 are pending. Claims 1-45 are withdrawn.
Response to Amendment
Applicant amended claim 46 and narrowed the scope of the immunomodulatory construct to consist of two different truncated T3SS bacterial effector polypeptides, and added the limitations of now canceled claim 48.
Applicant amended claims 49-51, 53-56, 58-61, 63, 65, 72-74, 82 and narrowed the scope of the construct.
Applicant amended claim 77, 80, and 83, and canceled claims 48, 64, and 66-68.
The objection to the disclosure is withdrawn in view of the amendment.
The rejection of claims 77-81 under 35 U.S.C. 112(b) is withdrawn in view of the amendment.
The rejection of claims 48, 64, and 67-68 under 35 U.S.C. 112(a) is withdrawn in view of the amendment.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 04/13/2026 is acknowledged and has been considered.
New Rejection Necessitated by the Amendment
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.
Claims 74-76 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 74 recites “wherein the truncated YopJ polypeptide consists of a point mutation at cysteine 172 of SEQ ID NO.: 7”. It is not clear how a polypeptide consists of a point mutation. Applicant may consider amending the claim to recite “wherein the truncated YopJ polypeptide is SEQ ID NO.: 7 with a point mutation corresponding to position C172” in order to obviate the rejection.
Claim 75 recites the limitation " The method of Claim 48" in line 1. The claim depends from a canceled claim. Applicant may consider amending the claim to depend from claim 46 in order to obviate the rejection.
Claim 76 depends from claim 75 and is also rejected.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 49-63, 65, 69-74, 77-81, and 83-87 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 49, 54, 59, 63, 69, and 72 do not further limit the subject matter of independent claim 46. Claim 46 limits the E3 ubiquitin ligase to IpaH 7.8 or IpaH9.8, the RhoGTPase modulator to YopE, the cysteine methyltransferase to OspZ or NleE, the zinc metalloprotease to NleC, the acetyltransferase to YopJ, the O-GlcNac transferase to NleB, and the LRR motif binding and sequestration polypeptide to YopM. However, claims 49, 54, 59, 63, 69, and 72 recite broader limitations of a truncated T3SS cysteine methyltransferase polypeptide, a truncated T3SS zinc metalloprotease polypeptide, a truncated T3SS O-GlcNac transferase, a truncated T3SS E3 ubiquitin ligase polypeptide, a RhoGTPase modulator, a cysteine methyltransferase, and a truncated acetyltransferase polypeptide, respectively.
Regarding claims 69, 77, and 83 do not further limit the subject matter of independent claim 46. Claim 46 recites “construct consists of two different truncated T3SS bacterial effector polypeptides”. However, dependent claim 69 recites “the immunomodulatory construct comprises” and the claim does not require the T3SS bacterial effector polypeptides to be truncated. Dependent claim 77 recites “the construct further comprises”. Claim 83 recites “truncated T3SS bacterial effector polypeptides are joined by a linker”. Claim 46 does not recite a linker. These dependent claims do not further limit the subject matter of claim 46. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claims 50-53, 55-58, 60-62, 65, 70-71, 73-74, 78-81, and 84-87, which dependent from claims 49, 54, 59, 63, 69, 72, 77, and 83, respectively, are also rejected.
Maintained Rejection
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 49-63, 65, 69-74, and 82-87 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for inhibiting cytokine release by E3 ubiquitin ligases lpaH7.8 and lpaH9 .8, does not reasonably provide enablement for treating a subject having an inflammatory disorder by administering a composition comprising a construct consisting of linked two truncated T3SS bacterial effector polypeptides. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In making a determination that a disclosure does not satisfy the enablement requirement, the factors that may be considered include: (A) the breadth of the claims, (B) the nature of the invention, (C) the state of the prior art, (D) the level of one of ordinary skill, (E) the level of predictability in the art, (F) the amount of direction provided by the inventor, (G) the existence of working examples, and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
Nature of the invention. The claims are drawn to a method of treatment of an inflammatory disorder in a subject, comprising administering a composition comprising linked two truncated T3SS bacterial effector polypeptides.
Breadth of the claims. The breadth of the claimed invention fails to receive adequate support in the specification. Claims 49-53 encompass treatment of inflammatory disorder in a subject by administering a construct consisting of a truncated YopM polypeptide linked to a truncated T3SS cysteine methyltransferase polypeptide. Claims 54-58 encompass treatment of inflammatory disorder in a subject by administering a construct consisting of a truncated YopM polypeptide linked to a truncated T3SS zinc metalloprotease polypeptide. Claims 59-62 encompass treatment of inflammatory disorder in a subject by administering a construct consisting of a truncated YopM polypeptide linked to a truncated T3SS O-GlcNac transferase. Claims 63 and 65 encompass treatment of inflammatory disorder in a subject by administering a construct consisting of a truncated first T3SS E3 ubiquitin ligase polypeptide linked to a truncated second T3SS E3 ubiquitin ligase. Claims 69-71 encompass treatment of inflammatory disorder in a subject by administering a construct comprising a RhoGTPase modulator linked to a cysteine methyltransferase. Claims 72-74 encompass treatment of inflammatory disorder in a subject by administering a construct consisting of a truncated YopM polypeptide linked to a truncated acetyltransferase polypeptide. Claims 82-87 encompass treatment of inflammatory disorder in a subject by administering an immunomodulatory construct consisting of a fusion protein of two truncated T3SS bacterial effector polypeptides joined by a linker.
State of the prior art and Unpredictability: Prior art Lubos (US-2016/0206713, published 07/21/2016, of record in IDS filed on 10/29/2021) teaches a method of treatment of an inflammatory disorder in a subject comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an isolated effector protein of a type III secretion system (T3SS) comprising a variant, fragment, or immunomodulatory domain of the effector protein (claims 1-2, and 31). 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 (claim 10). Ruter (USPN 8,840,901, published 09/23/2014, of record in Office correspondence mailed on 04/15/2025) teaches YopM modulates inflammatory reaction and teaches YopM can be linked to other cargo molecules like proteins, markers, and other effector YopP (Title, column 25 lines 58-60). Ruter is silent on the activity of the fusion protein. Paz (Molecular Biology Reports 51.1 (2024): 410, of record in Office Correspondence mailed on 04/15/2025) 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 therapeutical anti-inflammatory activity of the recited structures. Therefore, the claimed method of treating inflammatory disorder using the claimed linked proteins is highly unpredictable.
Guidance in the specification and working examples. The guidance in the specification is not commensurate in scope with the claimed invention. Example 1 discloses inhibition of cytokine release by E3 ubiquitin ligases lpaH7.8 and lpaH9 .8. FIGs 1-5 show the fusion protein sequences and structure but do not disclose functionality of the chimeric proteins in treating inflammatory disorder. Table 1 discloses the activity of single T3SS effectors. The specification fails to provide guidance pertaining to treating inflammatory disorder using the claimed polypeptides and fails to show any data to demonstrate an immunomodulatory activity of: truncated YopM polypeptide linked to a truncated T3SS cysteine methyltransferase polypeptide, truncated YopM polypeptide linked to a truncated T3SS zinc metalloprotease polypeptide, YopM polypeptide linked to a truncated T3SS O-GlcNac transferase, T3SS E3 ubiquitin ligase polypeptide linked to a truncated second T3SS E3 ubiquitin ligase, RhoGTPase modulator linked to a cysteine methyltransferase, or truncated YopM polypeptide linked to a truncated acetyltransferase polypeptide.
Amount of experimentation necessary. The above mentioned details establish that one skilled in the art would not be able to make or use the full scope of claimed invention with a reasonable expectation of success and without undue experimentation.
Taking these factors into account, undue experimentation would be required by one of ordinary skill in the art to practice the full scope of the claimed invention. Thus, the claims are not fully enabled by the disclosure.
Claims 46, 49, 54, 59, 63, 69, 72, and 77-88 remain 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.
The instant claims require a therapeutically effective amount of pharmaceutical composition comprising an immunomodulatory construct consisting of two different truncated T3SS bacterial effector polypeptides, wherein each truncated T3SS bacterial effector polypeptide consists of a portion of the corresponding full length T3SS bacterial effector polypeptide, wherein the T3SS bacterial effector polypeptide is 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 46 and 77-88 encompass any truncation of T3SS bacterial effector polypeptide. The specification has not described any conserved amino acid residues to retain the immunomodulatory function. Claim 49 encompasses any truncation of YopM polypeptide linked to any truncation of any T3SS cysteine methyltransferase polypeptide. Claim 54 encompasses any truncation of YopM polypeptide linked to any truncation of any T3SS zinc metalloprotease polypeptide. Claim 59 encompasses any truncation of YopM polypeptide linked to any truncation of any T3SS O-GlcNac transferase. Claim 63 encompasses any truncation of T3SS E3 ubiquitin ligase polypeptide.
Prior art Ruter (cited in the 103 rejection) discloses 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).
The prior art disclosure of a single 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 variant described in Ruter reference is 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 reference. 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. 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.
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 46, 77, 82, and 88 remain rejected and claims 80 and 81 are rejected under 35 U.S.C. 103 as being unpatentable over Lubos (US-2016/0206713, published 07/21/2016, of record in IDS filed on 10/29/2021, hereinafter “Lubos”).
Regarding claim 46, the limitation “a construct consisting of two or more truncated T3SS bacterial effector polypeptides” is given the broadest reasonable interpretation. As such, the limitation does not require the two peptides to be linked or fused.
Lubos teaches a method of treatment of an inflammatory disorder in a subject comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an isolated effector protein of a type III secretion system (T3SS), a variant, fragment, or immunomodulatory domain of the effector protein (claims 1-2, 10, and 31).
Lubos does not specifically teach two truncated T3SS bacterial effector polypeptides. However, 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, a fragment, or an immunomodulatory domain thereof (claims 2 and 10).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition taught by Lubos by adding a fragment of second effector protein as suggested by Lubos. One of ordinary skill in the art would be motivated to do so in order to target different inflammatory inducers. MPEP §2144.06(I) states that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, the idea of combining them flows logically from their having been individually taught in the prior art.
Regarding claim 77, Lubos teaches the effector proteins have a transduction domain ([0067]).
Regarding claims 80-81, Lubos teaches the composition comprises IpaH9.8 or a fragment thereof (claims 2 and 10) and teaches the sequence of IpaH9.8 which has a sequence 100% identical to amino acids 2-56 of instant SEQ ID NO.:11 (Figure 22, SEQ ID NO:9)
Regarding claim 82, Lubos teaches the effector proteins, variants, fragments, or immunomodulatory domains are linked to a cell-specific targeting agent and teaches the cell-specific targeting agent is antibody fusion proteins ([0168], [0174], [0176])
Regarding claim 88, Lubos teaches the pharmaceutical composition can be administered topically such as to the skin ([0278]) and teaches the pharmaceutical composition can treat inflammation such as psoriasis (i.e., skin disorder), gastroenteritis (i.e., gastrointestinal disorder), and arthritis (i.e., musculoskeletal disorder) ([0221]).
Claims 75-76 and 78-79 remain rejected under 35 U.S.C. 103 as being unpatentable over Lubos as applied to claim 46 above and further in view of Ruter (USPN 8,840,901, published 09/23/2014, of record in Office correspondence mailed on 04/15/2025), as evidenced by Appendix A (Sequence alignment of instant SEQ ID NO:19 and Ruter’s SEQ ID NO:2, of record in Office Correspondence mailed on 04/15/2025)
Regarding claims 75-76, Lubos does not teach truncated YopM.
However, Ruter teaches a composition comprising a truncated YopM used to treat inflammation (claims 1 and 11). Ruter teaches YopM has SEQ ID NO: 4 or SEQ ID NO: 2, and teaches truncated YopM comprises amino acids 1 to 133 of SEQ ID NO: 4 (column 19 lines 46-50, column 20 lines 34-35). Alignment of SEQ ID NO: 2 with instant SEQ ID: 19 shows overlapping sequences are 100% identical (See Appendix A for alignment).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the composition taught by Lubos by adding truncated YopM from amino acids 1 to 133 of SEQ ID NO:2 as suggested by Ruter. One of ordinary skill in the art would be motivated to do so in order to treat inflammation. MPEP §2144.06(I) states that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, the idea of combining them flows logically from their having been individually taught in the prior art.
Regarding claims 78-79, Ruter’s YopM with SEQ ID NO: 2 comprises instant SEQ ID NO:17. Ruter teaches amino acids residues from position 1 to 86 (i.e., instant SEQ ID NO: 17) are required for the autopenetration of YopM into the cytosol of the cell (column 55 lines 4-10).
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 46, 49-63, 65, 69-73, 75-83 and 88 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8, and 12 of US 12,404,307 in view of Lubos.
Regarding instant claims 46, 48-49, 75-77, and 82-83, 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 SspH1 protein transduction domain, or an lpaH protein transduction domain wherein the protein transduction domain and the set of paired peptides comprise a fusion protein and the amino acid sequence of the fusion protein is at least 85% identical to the sequence set forth in SEQ ID NO. 10, 13, 16, 19, 22, or 24. Recited SEQ ID NO. 10 comprises a fusion of truncated YopM and NleE, cysteine methyltransferase. patent claim 2 recites wherein the first bacterial effector polypeptide and the second bacterial effector polypeptide recognize are different. Patent claim 3 recites wherein a first bacterial effector polypeptide and the second bacterial effector polypeptide are immunomodulatory. Patent claim 4 recites wherein the first bacterial effector polypeptide and the second bacterial effector polypeptide recognize a different molecular target or modulate a different inflammatory pathway. Patent claim 6 recites wherein a linker is positioned between the first bacterial effector polypeptide and the second bacterial effector polypeptide.
Regarding instant claims 50-66, 69-73, and 80-81, patent claim 12 recites a composition comprising a protein transduction domain polypeptide linked to a first bacterial effector polypeptide and at least one additional bacterial effector polypeptides wherein the first bacterial effector polypeptide is a polypeptide having 90% sequence identity to an amino acid sequence set forth in the group consisting of SEQ ID NOs 3, 89, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78 and 79. Recited SEQ ID NO. 76 comprises instant SEQ ID NO: 3. Recited SEQ ID NO. 62 comprises instant SEQ ID NO: 5. Recited SEQ ID NO. 60 comprises instant SEQ ID NO: 9. Recited SEQ ID NO. 72 comprises instant SEQ ID NO: 11. Recited SEQ ID NO. 70 comprises instant SEQ ID NO: 1.
Regarding instant claims 78-79, patent claim 8 recites the protein transduction domain comprises SEQ ID NO. 5. SEQ ID NO. 5 is 100% identical to instant SEQ ID NO: 17.
Patent claims 1-4, 6, 8, and 12 do not recite administering the composition to treat an inflammatory disease.
However, Lubos teaches a method of treatment of an inflammatory disorder in a subject comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an isolated effector protein of a type III secretion system (T3SS) comprising a variant, fragment, or immunomodulatory domain of the effector protein (claims 1-2, and 31).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition recited in patent claims 1-4, 6, 8, and 12 by administering the composition to treat an inflammatory disorder as suggested by Lubos. Since patent claim 4 recites the compositon modulates inflammatory pathways and Lubos teaches bacterial effectors can be administered to treat an inflammatory disease, there is a reasonable expectation of success.
Regarding instant claim 67-68, patent claims 1-4, 6, 8, and 12 do not recite SEQ ID NO: 13. However, Lubos teaches pharmaceutical composition comprising effector and at least one Leucin-rich repeat such as IpaH4.5 to treat inflammatory disorder (claims 1 and 10) and teaches amino acids 63-270 of IpaH4.5 comprise the leucine rich repeat domain (Figure 20). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition recited in claim 1-4, 6, 8, and 12 by adding amino acids 63-270 of IpaH4.5 as suggested by Lubos. One of ordinary skill in the art would be motivated to do so in order to form a pharmaceutical composition to treat inflammation.
Regarding instant claim 88, Lubos teaches the pharmaceutical composition can treat inflammation such as psoriasis (i.e., skin disorder), gastroenteritis (i.e., gastrointestinal disorder), and arthritis (i.e., musculoskeletal disorder) ([0221]).
Claims 84-87 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8, and 12 of US 12,404,307 in view Ruter.
Regarding instant claims 84-87, patent claims 1-4, 6, 8, and 12 do not specify the linker. However. Ruter teaches fusion protein with YopM and a cargo molecule and teaches the cargo can be linked via a cleavable linker (column 24 lines 4-5). Ruter teaches linker is hydrazone linkage (i.e., linker comprises hydrazine) (column 24 lines 6-10), and teaches the cargo can be covalently linked (column 13 lines 12-17). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition recited in patent claims 1-4, 6, 8, and 12 by adding a cleavable linker or a hydrazone linker as suggested by Ruter. One of ordinary skill in the art would be motivated to do so in order to link the peptides.
Response to Arguments
Applicant's arguments filed 10/15/2025 have been fully considered but they are not persuasive.
Applicant argues the that specification, for example [0091], provides a description of immunomodulatory activity together with examples of such activity as associated with the identified T3SS bacterial effector polypeptides. Applicant argues that experimentation necessary to determine enablement is not undue, and that Applicant has specifically identified the individual components of the polypeptides so no experimentation is necessary in that regard.
In response to the argument, the specification does not contain a paragraph [0091]. The specification, para. [0019], discloses that bacterial effector polypeptides inhibit or disable host immune response, and Table 1 discloses the activity of single T3SS effectors. The specification fails to provide guidance pertaining to treating inflammatory disorder using the claimed polypeptides and fails to show any data to demonstrate an immunomodulatory activity of a truncated YopM polypeptide linked to a truncated T3SS cysteine methyltransferase polypeptide, truncated YopM polypeptide linked to a truncated T3SS zinc metalloprotease polypeptide, YopM polypeptide linked to a truncated T3SS O-GlcNac transferase, T3SS E3 ubiquitin ligase polypeptide linked to a truncated second T3SS E3 ubiquitin ligase, RhoGTPase modulator linked to a cysteine methyltransferase, or truncated YopM polypeptide linked to a truncated acetyltransferase polypeptide.
Applicants argues that the specification discloses that certain truncated T3SS effector polypeptides are capable of immunomodulatory activity, and that it provides guidance for assessing such activity.
In response to the argument and as Applicant stated, certain truncated T3SS effector polypeptides are capable of immunomodulatory activity. However, the genus claimed by Applicant is very large and encompasses any truncation of the T3SS effector polypeptides. The claim requires the truncated effector to have immunomodulatory. There is no disclosure as to which portion of any polypeptide is to be retained in order for the portion to have a useful effect, nor the effect of any specific combination of effector truncations. One skilled in the art would not be able to make or use the full scope of claimed invention with a reasonable expectation of success and without undue
experimentation.
Applicant argues that the provided FIGURES A-D show the activity of various polypeptide constructs as compared to YopM full length polypeptides.
In response to the argument, the resolution of FIGURES A-D does not permit the examination of the annotations needed to understand and discern the different constructs in each figure. Applicant may consider providing figures with higher resolution that clearly shows the annotations of the different constructs.
Applicant argues that Lubos does not teach any composition that comprises more than one type of effector protein and argues that Lubos is limited to "E3 ubiquitin ligase domain and optionally at least one Leucin-rich repeat. Applicant argues Lubos does not disclose the combination of multiple T3SS bacterial effector polypeptides or fragments thereof in a single construct. Applicant argues that Ruter is limited to compositions that consist of YopM, YopM, fragments, or YopM variants.
In response to the argument, Lubos teaches a pharmaceutical composition to treat inflammation comprising a fragment of an isolated effector protein of a type III secretion system (T3SS) selected from the group consisting of SspHl, SspH2, SlrP, IpaHl.4, IpaH2.5, IpaH3, IpaH4.5, IpaH7.8, and IpaH9.8. Ruter is relied upon for teaching truncated YopM and its role in regulating inflammatory reactions and that it can efficiently be used as an immunomodulatory or immunosuppressive agent. Claim 46 does not require the polypeptides to be fused or linked, and the claim requires the effectors to be different but does not exclude the different effectors to be from the same family of effectors. This is also supported by instant claim 63. Furthermore, different effectors can also be understood as same effector with different truncations.
MPEP §2144.06(I) states that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, the idea of combining them flows logically from their having been individually taught in the prior art. One of ordinary skill in the art would be motivated to combine two effectors taught by Lubos and Ruter in order to treat inflammation.
Applicant requests that the double patenting rejection over US 12,404,307 be held in abeyance. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). Thus, the double patenting rejections of record have been maintained as no response to these rejections has been filled by applicant at this time.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MARY A CRUM/ Examiner, Art Unit 1657
/THANE UNDERDAHL/ Primary Examiner, Art Unit 1699
Prosecution Insights