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
The amendment after non-final office action filed October 23, 2025 is acknowledged. Claims 2-8, 12-13 were cancelled, claims 1, 9, 11, 15, 17-18 were amended, claims 19-20 were newly added and claims 1, 9-11, 14-20 are pending.
*After further review, a second Non-final follows.
Election/Restrictions
The restriction requirement was deemed proper and made FINAL previously. Claims 1, 9-11, 14-20 are examined on the merits of this office action.
Declaration under 37 C.F.R. 1.132
The Declaration under 37 CFR 1.132 filed October 23, 2025 is sufficient to overcome the rejection of claims 1, 8-11, 14-18 over Andreelli (US20160058833, published 3/3/2016) as evidenced by Ghosh (Nature Reviews, Gastroenterology and hepatology, volume 19, 2022, pages 565-579) because Applicants have provided evidenced that aging population does not necessarily have microbiota imbalance and decreased gram positive protective bacteria.
Withdrawn Objections/Rejections
The rejection of Claim(s) 1, 8-11, 14-18 under 35 U.S.C. 102 (a)(1) as being anticipated by Andreelli (US20160058833, published 3/3/2016) as evidenced by Ghosh (Nature Reviews, Gastroenterology and hepatology, volume 19, 2022, pages 565-579) is withdrawn in view of Applicant’s arguments filed October 23, 2025.
Maintained/Revised Rejections
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, 9-11, 14-20 are/remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 14-22 of co-pending Application No. 18/495355 (reference application) as evidenced by Ghosh (Nature Reviews, Gastroenterology and hepatology, volume 19, 2022, pages 565-579). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims a method of treating destruction of gut microbiota balance resulting from a cause selected from the group consisting of medication (not antibiotics), chemotherapy, radiotherapy, poor nutrition, and aging comprising administering a Reg3a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO:3, and SEQ ID NO: 4 to a host in need thereof having a decreased proportion of immune protective gram-positive bacteria, wherein the Reg3a polypeptide protects oxygen sensitive gram-positive bacteria” (see claim 1). Instant claim 9, claims protecting specific gram positive bacteria (clostridiales, ruminococcaceae); oral administration (claim 10); treating alterations or changes in gut microbiota with a decreased proportion of gram positive bacteria (claim 11) administering Reg3a (Claim 11); protect against different gram positive bacteria (claims 14-18) and detecting protective gram positive bacteria prior to administration (see claims 19-20).
Co-pending Application 18/495355 claims “A method of treating or preventing a microbiota-related disease and/or disorder selected from the group consisting of inflammatory bowel disease (IBD), colitis, gastrointestinal infections, irritable bowel syndrome, gastrointestinal functional diseases, gastrointestinal tract cancer, metabolic syndrome, obesity, diabetes, liver diseases, allergic diseases, neurodegenerative diseases, psychological disorders, autoimmune disease, cystic fibrosis, atopic dermatitis, neurological disease, autism, anxiety, depression, chronic pain, Alzheimer's disease and Parkinson's disease, said method comprising administering to a patient in need thereof an effective amount of the composition according to claim 1” (see claim 6) wherein the composition of claim 1 is the same peptides of the instant claims in combination with gram positive bacteria that is oxygen sensitive.
Co-pending Application 18/495355 further claims “A method for preventing or treating destruction of gut microbiota balance resulting from a cause selected from the group consisting of medication, antibiotics, chemotherapy, radiotherapy, immunotherapy, poor nutrition, eating disorders, illness, aging, and genetics comprising administering to a patient in need thereof an effective amount of the composition of claim 1” (see claim 7); oral administration (claim 3) and protecting gram positive bacteria.
Regarding the limitations of “wherein the Reg3a polypeptide protects oxygen sensitive gram positive bacteria (instant claims 1, -9 and 14-18, all the different species of gram positive bacteria); Co-pending Application 18/495355 claims the same method of the instant claims including the same patient population (patients as defined by applicant that have altered gut microbiota and reduced gram positive bacteria) and administering the same therapeutic and thus, these effects will inherently occur as a results of practicing the method of Co-pending Application 18/495355. As evidenced by Ghosh, Ghosh teaches that “the microbiome has a reciprocal relationship with age: it changes as the host ages and is altered in age-related disease, but it also modifies age-related impairment of the host” (see also Figure 1) and also inclusive to changes in gram positive bacteria in the gut (see Figure 3). Thus, with aging there is a change of gut microbiota balance and this is inherent to the aging process which includes changes in gram positive bacteria (bifidobacterium for example). Furthermore, the co-pending application further claims patients undergoing chemotherapy, radiotherapy and poor nutrition all of which Applicants admits these specific patient populations are associated with decreased immune protective gram positive bacteria. Co-pending application further defines disruption of the balance to comprise reducing of immune protective bacteria (“essentially gram positive”) (see paragraph 0009, PGPUB). Furthermore, the goal is the same, to protect the immune protecting gram positive bacteria. Accordingly, it would have been an obvious variant of the co-pending claimed method to expressly recite that the treated subject has a decreased proportion of immune protective gram positive bacteria, since this represents an inherent or expected condition of the same subjects already being treated by the same method.
Regarding claims 19-20, the additional detecting step recited in instant claims 19-20 constitutes routine microbiota assessment of the same patient populations already treated in the co-pending claims and would have been an obvious variant of the method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicant will address this rejection when the final outcome of the claims in the present or co-pending application is determined. Thus, the rejection is maintained.
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 1, 9-11, 14-20 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 claims “A method of treating destruction of gut microbiota balance resulting from a cause selected from the group consisting of medication, chemotherapy, radiotherapy, poor nutrition, and aging… comprising administering a Reg3a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO:3, and SEQ ID NO: 4 to a host in need thereof having a decreased proportion of immune protective gram-positive bacteria, wherein the Reg3a polypeptide protects oxygen sensitive gram-positive bacteria.” Claim 11 claims “characterized by having a decreased portion of immune protective gram positive bacteria…”
The phrase “immune protective gram positive bacteria” in instant claims 1 and 11, lacks clear boundaries and renders the scope of the claim indefinite. The functional component of “immune protective” is not defined in the specification with sufficient clarity or objective criteria to inform a person of ordinary skill in the art of the scope of the claim. In particular, Applicant’s specification states “Yet microbiota imbalance which comprises increased microbial biomass at the mucosal level, increased proportions of immuno-aggressive bacteria (essentially Gram negative) and, conversely, decreased proportions of immuno-protective bacteria (essentially Gram positive)” (See paragraph 0009). The term “immune protective” is subjective and could refer to a variety of different mechanism. It is unclear (especially in light of the specification) which functions or mechanisms qualify a gram positive bacterium as immune protective. Furthermore, some gram positive bacteria can have positive effects on the immune system but can also be pathogenic in other scenarios which further adds to the confusion and lack of clarity. Applicant should particularly point and distinctly claim their invention.
Claims 9-10, 14-19 and claim 20 are also rejected due to their dependence on claims 1 and 11 and not further clarifying these points of confusion.
Response to Applicant’s Arguments
Applicant argues that two references (Kelly and Kandasamy) provided show that one of ordinary skill in the art would readily understand what is meant by “immune protective gram positive bacteria”. It was known that such bacteria produce metabolites, in particular short chain fatty acids, able stimulate the immune response.
Applicants arguments have been fully considered but not round persuasive. While the cited art references describe that certain gram positive commensal or probiotic bacteria may produce metabolites that modulate immune function, these teachings do not provide an objective boundary for determining which gram positive bacteria qualify as “immune protective” within the scope of the claims. Gram positive bacteria comprise a broad and heterogenous class that includes organisms with beneficial, neutral, and pathogenic effects depending on strain, host condition and context. The fact some gram positive bacteria are reported to produce immune modulating metabolites does not establish that all, or even clearly bounded subset are immune protective. Neither the claims nor the specification provide objective criteria, thresholds or defined lists of taxa by which bacterium is determined to be “immune protective”. The specification instead states that immune protective bacteria are “essentially gram positive”, which further broadens the scope, because gram positive status alone does not correspond to a uniform immune protective function. Accordingly, even in view of Kelly and Kandasamy, one of ordinary skill in the art would not be able to determine with reasonable certainty which bacteria fall within the claimed category.
New Rejections
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, 9-11, 14-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while the specification is enabling for administration of Reg3a peptide and demonstrates protection of certain identified oxygen sensitive gram positive gut bacteria under defined experimental and inflammatory gut model conditions, is not enabled for protection across the full claimed scope of immune protective gram positive bacteria across all recited etiologies and patient populations without undue experimentation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to methods of treating destruction of gut microbiota balance in a host by administering a Reg3a polypeptide, wherein the method applies across multiple patient populations and etiologies including chemotherapy, radiotherapy, aging, and poor nutrition, and wherein the Reg3a polypeptide protects oxygen sensitive immune protective gram positive bacteria. The claims therefore encompass a broad range of bacterial taxa, disease etiologies and patient conditions. The claims are broad in that they encompass protection of immune protective gram positive bacteria as a class, protection of oxygen sensitive gram positive bacteria broadly, treatment across multiple unrelated etiologies (chemo, radiotherapy, aging, poor nutrition), use across unspecified patient populations, without specific limitation to specific bacterial species, genera, or defined functional thresholds. The breadth covers numerous gram positive taxa with differing physiological and immunological roles and multiple distinct clinical contexts and microbiota disruption.
The invention concerns host microbiome interactions and microbial community protection, which is a biologically complex and variable field. The behavior of gut microbial taxa in response to host peptides, oxidative stress, chemotherapy, inflammation, nutrition state is known to be context dependent and organism specific. Functional responses of different gram positive taxa are not uniform or predictable across species or conditions.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The prior art recognizes that gram positive gut commensals are heterogenous in immune function, probiotic and immune effects are strain specific and context dependent (as show in Kelly and Kandasamy, cited and provided by Applicant).
Zhang teaches “In summary, the overexpression of Reg3A, a protein mainly expressed in the digestive system, has been demonstrated in many kinds of gastrointestinal cancer, including hepatocellular carcinoma, pancreatic cancer, gastric cancer, and colorectal cancer. Up to date, a large amount of evidence have shown that Reg3A mediates diverse functional effects under cancer conditions, including cell proliferation promotion, cell apoptosis inhibition, the regulation of cancer cell migration and invasion. In particular, based on the significant up-regulation of Reg3A during pancreatic inflammation as well as its tumorigenic potential, Reg3A has been believed to play a key role in inflammation-linked pancreatic carcinogenesis. Therefore, Reg3A could be used as a tumor biomarker for gastrointestinal malignancy and as a promising target for prevention and treatment” (See conclusion).
Furthermore, Murkherjee (cited previously) teaches that “REG3akillsGram-positivebacteria by first binding to peptidoglycan, then oligomerizing to form a hexameric membrane-penetrating pore that is stabilized by electrostatic interactions between REG3a cationic residues and the anionic phospholipids of the bacterial membrane” (See Figure 1 description). The art does not establish that Reg3a broadly protects all immune protective bacteria across taxa and etiologies. Thus, the prior art does not supply the missing full scope enablement.
The art is relatively unpredictable of the art. The art is relatively unpredictable. The specification and applicant cited literature indicate that immune and probiotic effects are strain specific, responses differ across bacterial families, not all gram positive taxa exhibit the same immune behavior, microbiome responses vary by disease context and host condition. The specifications own data show variable abundance effects across gram positive families, indicating non uniform response.
(5) The relative skill of those in the art:
The relative skill of those in the art regarding the claimed methods is high. However, even a skilled artisan would recognize substantial variability across bacteria taxa and patient conditions. Skill in the art does not eliminate the need for validation across the full claimed bacterial and etiological scope.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification provides limited guidance including experimental data in a specific disease model context, limited recombinant peptide exposure, examples involving a small number of gram positive taxa, no general rule or predictive criteria for identifying which gram positive organisms will be protected, no framework for selecting responsive taxa and no cross etiology dosing or response guidance. Working examples are present but narrow in scope.
In the instant case, Applicants reduce to practice human Reg3alpha (SEQ ID NO:4) and show promoting growth of specific oxygen sensitive gram positive bacteria (see Examples 1-4). Instant SEQ ID NO:1 is SEQ ID NO:4 with a signal sequence, SEQ ID NO:3 is the mature human Reg3alpha without signal sequence and SEQ ID NO:4 is the naturally occurring mature human protein after tryptic cleavage. Example 2 showed that recombinant Reg3a did not improve DSS-induced colitis in WT mice contrary to hReg3a transgenic mice thus contributing to unpredictability. Example 4 shows that intrarectal administration of hReg3a decreased colon damage and inflammation in WT mice with colitis
The specification includes working examples demonstrating that Reg3α peptide can affect survival or relative abundance of certain oxygen-sensitive gram-positive gut bacteria under specific experimental conditions. In particular, the disclosure provides experimental data involving recombinant or transgenic Reg3α and shows protective or abundance increasing effects for selected anaerobic gram-positive commensal taxa, including Faecalibacterium prausnitzii and Roseburia intestinalis, and reports family level microbiome shifts including increases in Ruminococcaceae under an inflammatory gut model.
However, the working examples are limited in taxonomic and contextual scope. The disclosure does not provide representative working examples across the full breadth of the claimed class of “immune-protective gram-positive bacteria” or across the full range of claimed etiologies (chemotherapy, radiotherapy, aging, and poor nutrition). The experimental data are confined to specific species and specific model conditions and do not establish that the reported protective effect applies broadly across gram-positive taxa. Further, the specification’s own microbiome composition data indicate variability among gram-positive bacterial families, with some gram-positive groups not showing uniform protective or abundance responses. This variability demonstrates that the effect of Reg3α is not shown to be consistent across gram-positive taxa and underscores that the working examples are not representative of the full claimed bacterial class. Accordingly, while the specification contains working examples for certain identified organisms and conditions, those examples are narrow relative to the breadth of the claims and do not reasonably enable the full scope without additional extensive experimentation.
(8) The quantity of experimentation necessary:
The quantity of experimentation required to practice the full scope of the claimed invention would be substantial. The claims encompass protection of immune protective gram-positive bacteria across multiple taxa and across several distinct etiologies of microbiota disruption, while the specification provides working data for only a limited number of bacterial species and model conditions. A person of ordinary skill in the art would need to perform extensive additional screening across gram-positive taxa, patient conditions, and disruption etiologies to determine which organisms are protected and under what conditions. Such broad, multi-factor testing exceeds routine optimization and constitutes undue experimentation relative to the scope of the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 19-20 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement (new matter). The claim(s) 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(s), at the time of the application was filed, had possession of the claimed invention.
Claims 19-20 recite a step of detecting decreased proportion of immune protective gram positive bacteria in the host prior to administering the Reg3a polypeptide.
Lack of Ipsis Verbis Support
The originally filed specification does not describe a method comprising a step of detecting, in a subject, a decreased proportion of immune-protective gram-positive bacteria as a prerequisite or decision step prior to administration of a Reg3α polypeptide.
While the specification includes experimental data characterizing microbiota composition in animal models, including comparisons between control and transgenic mice and measurements of bacterial populations under colitis or other experimental conditions, these disclosures are limited to research measurements and comparative experimental outcomes. They do not describe or suggest a claimed treatment method that includes performing a diagnostic or detection step in an individual host, and using the detection result to determine or precede administration of Reg3α polypeptide.
Thus, such limitations recited in the present claims, which did not appear in the specification, as filed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C. §112. Applicant is required to cancel the new matter in the response to this Office Action. Alternatively, applicant is invited to provide sufficient written support for the “limitations” indicated above. See MPEP §714.02, §2163.05-06 and §2173.05(i).
Lack of Implicit or Inherent Support
“While there is not in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure.” See MPEP 2163. Thus support can be furnished implicitly or inherently for a specifically claimed limitation. Although the specification reports relative abundance and CFU data for certain bacterial families in experimental settings, such disclosure does not inherently or implicitly provide written description support for a method step requiring detection in a host prior to treatment. There is no disclosure of a diagnostic assay step as part of the treatment method, evaluating whether a subject has a decreased proportion of immune-protective gram-positive bacteria before administration, or selecting subjects for Reg3α treatment based on such detection.
Accordingly, the newly added detecting limitations in claims 19–20 introduce subject matter not described in the specification as originally filed and therefore constitute new matter. Applicant is required to cancel or amend the claims to remove the unsupported subject matter, or point to clear written description support in the originally filed specification for the newly recited detecting step.
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654