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 4-5, 7-8, 10-11, 13-17, 19-23, 25-27, 29-31, 33-35, 37-39, 41-42, 44-50, 52-55, 57-59, 61-63, 65-73, 75-77, 79-80, 82-84, 86-87, 89, 91, and 93-95 are canceled.
Claims 1-3, 6, 9, 12, 18, 24, 28, 32, 36, 40, 43, 51, 56, 60, 64, 74, 78, 81, 85, 88, 90, and 92 are pending.
Claims 2-3, 6, 28, 32, 36, 40, 43, 51, 56, 60, 64, 74, 78, 85, 88, 90, and 92 are withdrawn from consideration.
Claims 1, 9, 12, 18, 24, and 81 are elected and examined herein.
Claims 1, 9, 12, 18, 24, and 81 are rejected.
Election/Restrictions
Applicant's election with traverse of inventions I in the reply filed on 03/02/2026 is acknowledged. The traversal is on the ground(s) that claim 1 has been amended to combine inventions I and III into a single invention and therefore claims encompassed by both groups I and III should be examined. In view of Applicant’s amendments, this is found persuasive. Claim 24 is joined with the claims of invention I, and claims 1, 9, 12, 18, 24, and 81 are therefore elected and examined herein.
Applicant's election with traverse of SEQ ID NOs: 29 and 32 in the reply filed on 03/02/2026 is acknowledged. The traversal is on the ground(s) that the NCBI GenBank Accession Nos. do not teach or suggest each and every element of the pending claims, nor has the Examiner provided sufficient reasoning as to how these NCBI GenBank Accession Nos. would guide or motivate one of skill in the art to arrive at the pending claims. As such, the claims have unity of invention. This is not found persuasive because the each species represents a distinct, unique and exclusive structure that requires a separate search of the prior art.
The requirement is still deemed proper and is therefore made FINAL.
Priority
Application No. 18/570,935 filed on 02/15/2023 is a 371 of PCT Application No. PCT/US2022/035575 filed on 06/29/2022, and also claims priority to provisional Application No. 63/216,365 filed on 06/29/2021.
Improper Markush Grouping
Claims 13 and 14 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of i. SEQ ID NOs: 28, 29, and 33 (in claim 12), and ii. SEQ ID NOs: 30, 31, 32, and 34 (in claim 14) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Claim 1 requires the gluten polypeptide comprise the sequence of SEQ ID NO: 1 (having at least 85% sequence identity), then further requires the gluten polypeptide have an ISG amino acid sequence that comprises SEQ ID NO: 7 (having at least 85% sequence identity), SEQ ID NO: 28, or SEQ ID NO: 29.
Claim 12 further requires the ISG comprise the amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 29, and 33. SEQ ID NOs: 28 and 29 have 95% sequence identity. However, the introduction of SEQ ID NO: 33 produces an improper Markush grouping. An alignment of SEQ ID NO: 33 to SEQ ID NOs: 28 reveals a sequence identity of 22%, and NCBI failed to provide any alignment between SEQ ID NO: 30 and SEQ ID NO: 29. The specification also discloses SEQ ID NO: 33, named gld-4, is from high molecular weight glutenin and not alpha-gliadin. Thus, SEQ ID NO: 33 is not structurally similar to the other sequences in the group.
Alignment of SEQ ID NO: 33 (query) to SEQ ID NO: 28 (Sbjct):
Query 2 CCQQL 6
CCQQL
Sbjct 43 CCQQL 47
Similarly, claim 18 provides a list of mutated sequences (SEQ ID NOs: 30, 31, 32, and 34) that are based on non-mutated SEQ ID NOs: 28, 29, and 33 recited in claim 12. The sequence of SEQ ID NO: 34 is a mutated version of SEQ ID NO: 33. It does not share structural similarity to the other sequences in the group for the same reasons provided above.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
Indefiniteness
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 1, 9, 12, 18, 24, and 81 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 1 recites:
“…wherein the ISG comprises:
an amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 7;
(ii) ILQQILQQQLIPCRDVVLQQHNIAHGSSQVLQQSTYQLLQQLCC QQLWQIPEQSRCQAIHNVVHAIILHQQQQQ (SEQ ID NO: 28); or
(iii) LWQIPEQSRCQAIHNVVHA (SEQ ID NO: 29)…”
However, SEQ ID NO: 28 is disclosed in the specification as a consensus alpha gliadin nrr1 sequence (Table 2 and 3), SEQ ID NO: 7 is disclosed as a ISG sequence that appears to be within the nrr1 region (with some sequence variation), and SEQ ID NO: 29 is within the ISG region of SEQ ID NO: 7 (with some sequence variation). That is, SEQ ID NO: 28 appears to be a nrr1 sequence comprising an ISG sequence. This is contradictory to the claim language that claims SEQ ID NO: 28 is comprised within an ISG sequence. Therefore, the claim is unclear and indefinite.
Claims 9, 12, 18, 24, and 81 are also rejected as a function of their dependency.
Claim 81 recites:
The method of claim 1, wherein the gluten polypeptide with a reduced inflammatory potential comprises:
(a) a reduced ability to remodel a cell membrane;
(b) a reduced ability to access an endosomal compartment within a cell;
(c) a reduced ability to mediate organization of innate immune ligands into ordered nanocrystalline structures;
(d) a reduced ability to promote activation of Toll-Like Receptors (TLRs); and/or
(e) a reduced ability to self-assemble into amyloidal or protofibril structures to activate formyl peptide receptor-like 1 (FPRL1) and/or formyl peptide receptor 2 (FPR2), as compared to a gluten polypeptide without the one or more alterations in the ISG.
It is unclear if each of (a)- (e) are required, or if only at least one of (a)- (e) is required for the limitations of the claim to be met. For this reason, the metes and bounds of claim 81 is unclear.
Improper Dependency
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.
Claim 12 and 18 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.
Claim 1 requires the ISG sequence comprise SEQ ID NO: 7 (at 85% sequence identity), 28, or 29, and introducing a mutation into the sequence. Claim 12 depends from claim 1 and requires the ISG comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 33. Unlike the other sequence identifiers, SEQ ID NO: 33 was not previously recited as an ISG sequence to be mutated/ altered in claim 1. By including SEQ ID NO: 33 in the group in claim 12, the scope of claim 12 is broadened rather than further limited, thus is of improper dependent form for failing to further limit the subject matter.
Similarly, claim 18 includes SEQ ID NO: 34 which is a mutated sequence of SEQ ID NO: 33 and is therefore rejected for the same reasons above.
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.
Written Description
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, 9, 12, 24, and 81 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.
Claims 1, 9, 12, 24, and 81 are broadly drawn to introducing any one or more alterations in an ISG sequence having at least 85% identity to SEQ ID NO: 7, or the ISG sequence of SEQ ID NO: 28 or 29 to produce a modified gluten polypeptide that has reduced inflammatory potential.
Applicant describes in working examples mutating the sequence of SEQ ID NO: 29 (gld-1) by replacing a single cationic arginine (R) with a non-cationic amino acid Glutamin (Q) to produce SEQ ID NO: 31 (gld-2) (see p. 81, Table 2, and ¶0259). Applicant also describes mutating SEQ ID NO: 29 (gld-1) plus the 4 bp directly upstream the sequence of SEQ ID NO: 29 (as seen in SEQ ID NO: 28) by replacing a cationic arginine (R) and a cationic Histidine (H) each with a non-cationic amino acid Glutamin (Q) to produce SEQ ID NO: 32 (gld-3) (see p. 81, Table 2, and ¶0259). Applicant describes that these mutated sequences associated with E. coli dsDNA (example of PAMP readily available in gastrointestinal tract (spec., ¶0252)), but were unable to form ordered nanocrystalline structures with the dsDNA that promotes binding of TLR9s for TLR9 activation and amplification of an immune response (¶0252-0253). Applicant further describes gld-2 and gld-3 elicited attenuated production of interleukin-8 (an immunogenic protein) in the presence of dsDNA as compared to gld-1 (Fig. 3, ¶0262).
Applicant also describes mutating a portion of the sequence of SEQ ID NO: 28 (gld-1) by replacing Cysteines (C) with Alanines (A) to produce SEQ ID NO: 30 (gld-1A) (see p. 81, Table 2, and ¶0263). Applicant describes these mutations to have reduced the dsDNA-peptide complex activity compared to the dsDNA-gld-a complex, and also elicited attenuated production of interleukin-8 in the presence of dsDNA as compared to gld-1 (¶0263, Fig. 3).
Aside from these 3 examples that mutations to a sequence 100% identical to SEQ ID NO: 29, thereby producing sequences 100% identical to instant SEQ ID NOs: 30-32, Applicant has not described any other example of any mutation that produces a modified gluten polypeptide that has reduced inflammatory potential. Applicant also does not describe any mutation in the upstream regions of SEQ ID NO: 7 and SEQ ID NO: 28 that produces a modified gluten polypeptide that has reduced inflammatory potential.
Claim 81 is further broadly drawn the method of claim 1, wherein the gluten polypeptide with a reduced inflammatory potential comprises: (a) a reduced ability to remodel a cell membrane; (b) a reduced ability to access an endosomal compartment within a cell; (c) a reduced ability to mediate organization of innate immune ligands into ordered nanocrystalline structures; (d) a reduced ability to promote activation of Toll-Like Receptors (TLRs); and/or (e) a reduced ability to self-assemble into amyloidal or protofibril structures to activate formyl peptide receptor-like 1 (FPRL1) and/or formyl peptide receptor 2 (FPR2), as compared to a gluten polypeptide without the one or more alterations in the ISG.
As stated above, Applicant describes two specific mutated sequences of SEQ ID NO: 29 that were unable to form ordered nanocrystalline structures with the dsDNA that promotes binding of TLR9s for TLR9 activation and amplification of an immune response (¶0252-0253). Applicant further describes 3 examples of mutated sequences that elicited attenuated production of interleukin-8 in the presence of dsDNA as compared to gld-1 (¶0262-0263, Fig. 3).
Applicant has not described any example of (a), (b), or (e). Applicant has not described any other mutation aside from the two mutated sequences that reduces organization of innate immune ligands into ordered nanocrystalline structures, nor any other mutated sequences that reduce the ability to promote activation of TLRs. Applicant has not described reduced activation of any TLR other than TLR9 as well.
The prior art fails to remedy this deficiency. There is a dearth of description in the prior art of mutations to these ISG sequences, altogether, much less mutations to these sequences that would confer reduced inflammatory as recited in claim 1 and any specific function recited in claim 81. Therefore, the prior art also fails to describe mutations to these sequences that could be expected to reduce inflammatory potential of the gliadin polypeptide. Furthermore, even years after the filing of the instant Application, Patt (Patt, Y. S., Lahat, A., David, P., Patt, C., Eyade, R., & Sharif, K. (2023). Unraveling the immunopathological landscape of celiac disease: a comprehensive review. International Journal of Molecular Sciences, 24(20), 15482.) highlights much is still unknown regarding celiac disease (CD).) Patt describes immune responses associated with celiac disease are complex, and there are still gaps in knowledge and unknown factors that contribute to the exact mechanisms and immune-pathophysiology of this immune response (abstract, p. 2, ¶1-2). Patt describes these gaps in the knowledge partially persist due to the complexity of immune responses, genetic variations, environmental influences, and their interplay in disease manifestation (p. 2, ¶2). Therefore, given the vast scope of claims 1 and 81, and the dearth of description in the art of mutations to these sequences that reduce inflammatory potential and the complexity of immune responses, the prior art does not remedy Applicant’s failure to fully describe the scope of the claims.
Because the full scope of mutations to the recited sequences that reduce inflammatory potential was unknown and unpredictable at the time of filing, and given the complexity and various factors of immune responses, Applicant could not have described the full genus of mutations in the sequences recited in SEQ ID NO: 1 that are capable of producing a modified gluten polypeptide that has reduced inflammatory potential. Therefore, the specification fails to provide an adequate written description to support the claim of any mutation to the sequences that produces a modified gluten polypeptide that has reduced inflammatory potential. The limited examples of 3 mutant sequences does not describe the claimed genus by virtue of example. Therefore, one of ordinary skill in the art would not have recognized the Applicant to be in possession of the claimed invention at the time the application was filed.
Closest Prior Art
Claims 1, 9, 12, 18, 24, and 81 appear to be free of the prior art.
Regarding claims 1, 9, 12, 18, 24, and 81, the closest prior art is Jouanin (Jouanin, A., Schaart, J. G., Boyd, L. A., Cockram, J., Leigh, F. J., Bates, R., ... & Smulders, M. J. (2019). Outlook for coeliac disease patients: towards bread wheat with hypoimmunogenic gluten by gene editing of α-and γ-gliadin gene families. BMC plant biology, 19(1), 333.). Jouanin teaches using CRISPR/Cas9 to introduce mutations into α-gliadin protein sequences either upstream the coeliac disease (CD) epitopes or within the CD epitopes that are located in the repetitive domain of the polypeptide for the purpose of inducing in- or out- of frame mutations that produce gliadin-knockouts or non-immunogenic gliadins (p. 2, ¶3, Fig. 1). However, Jouanin does not teach, suggest, or otherwise render obvious introducing one or more alterations in: i. an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7, ii. SEQ ID NO: 28, or iii. SEQ ID NO: 29 to produce a gluten polypeptide with a reduced inflammatory potential. This is because the instant sequence identifiers appear to be located within the first non-repetitive domain (also termed nrr1, nr1, non-repetitive region 1, n-terminal non-repetitive domain, or unique domain 1) which is downstream the regions targeted by Jouanin, and Jouanin does not teach, suggest, or otherwise render obvious mutating this region to reduce the inflammatory potential of the α-gliadin protein.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA N STOCKDALE whose telephone number is (703)756-5395. The examiner can normally be reached M-F 8:30-5:00 CT.
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, Amjad Abraham can be reached at (571) 270-7058. 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.
JESSICA N. STOCKDALE
Examiner
Art Unit 1663
/JESSICA NICOLE STOCKDALE/Examiner, Art Unit 1663
/CHARLES LOGSDON/Primary Examiner, Art Unit 1662
Prosecution Insights