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 to the claims filed after non-final office action on April 29, 2026 is acknowledged. Claims 1, 11 were amended, claims 2-8, 12-13, 19-20 were canceled and claims 1, 9-11, 14-18 are pending in the instant application. The restriction was deemed proper and made final previous office action.
The was restriction deemed proper and made FINAL in the previous office action. Claims 1, 9-11, 14-18 are examined on the merits of this office action. *After further review a second non-final follows due to a new rejection under 112(b) second paragraph.
Withdrawn Rejections/Objections
The rejection of claims 1, 9-11, 14-20 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claims filed April 29, 2026.
The rejection of claims 19-20 under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement (new matter) is withdrawn in view of amendment of the claims filed April 29, 2026.
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.
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Claims 1, 9-11, 14-18 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). Claim 1 was amended to require the gram positive bacteria to be decreased selected from Ruminococcaceae and Lachnospiraceae family. Instant claim 9, claims protecting specific gram positive bacteria (ruminococcaceae); oral administration (claim 10); treating alterations or changes in gut microbiota with a decreased proportion of gram positive bacteria elected from Ruminococcaceae and Lachnospiraceae family (claim 11) administering Reg3a (Claim 11); protect against different gram positive bacteria (claims 14-18).
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. Co-pending Application 18/495355 further claims wherein the gram positive bacteria are Ruminococcaceae and/or Lachnospiraceae (see claims 11, 19-20).
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 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, 14-18 remains 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 clams 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 medication, chemotherapy, radiotherapy, poor nutrition, and aging. Excluding antibiotics. The claims further require that he host has a decreased proportion of immune protective gram positive bacteria selected from the Ruminococcaceae family and the Lachnospiraceae family, as compared to a healthy individual, and that the Reg3a polypeptide protects oxygen sensitive gram positive bacteria. Although the bacterial limitation narrows the claimed patient population, the claims remain broad because they encompass treatment of gut microbiota imbalance generally across multiple unrelated etiologies and patient populations. The added bacterial family limitation defines a characteristic of the patient rather than limiting the treatment to restoration or protection of only those bacterial families. With respect to claim 11, although the claim is phrased as treating alterations or changes in the composition and or biodiversity of the gut microbiota, the claim likewise is not limited to treating the decreased Ruminococcaceae and or Lachnospiraceae populations themselves. Rather, the recited bacterial family limitation defines a characteristic of the patient population, while the claimed therapeutic objective remains treatment of gut microbiota dysbiosis generally. Accordingly, the enablement analysis applies equally to claim 11.
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.
Neither the prior art nor the specification established that Reg3a predictably treats gut microbiota imbalance across the full range of claimed etiologies whenever a patient exhibits decreased Ruminococcaceae and/or Lachnospiraceae. Responses of microbiota remain context, strain and disease dependent.
(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 across the full scope of the claimed methods for treating gut microbiota imbalance resulting from medication, chemotherapy, radiotherapy, poor nutrition and aging. Rather, the experimental data are confined to selected organisms and limited disease models. Although the amended claims require that the patient exhibit decreased proportions of bacteria belonging to the Ruminococcaceae and/or Lachnospiraceae families, the specification does not establish that treatment of gut microbiota imbalance across the full scope of the claimed etiologies is enabled whenever the patient characteristic is present.
(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 treatment of gut microbiota imbalance resulting from multiple distinct etiologies in patients exhibiting decreased Ruminococcaceae and/or Lachnospiraceae. The specification provides working data for only limited experimental models and selected bacterial organisms. A person of ordinary skill in the art would need to perform substantial additional experimentation to determine whether the claimed treatment is effective across the full range of claimed etiologies and patient populations. Such testing exceeds routine optimization and constitutes undue experimentation relative to the scope of the claims.
Response to Applicant’s Arguments
Applicants argue that claims 1 and 11 have been amended to limit the immune protective gram positive bacteria to the Ruminococcaceae and Lachnospiraceae families, thereby significantly narrowing the claim scope and addressing the Examiner’s enablement concerns.
Applicant’s arguments have been fully considered but not found persuasive. Although the amendments narrow one characteristic of the claimed patient population, the claims remain directed to methods of treating destruction of gut microbiota balance generally resulting from medication, chemotherapy, radiotherapy, poor nutrition and aging. The added bacterial family limitation defines a characteristic of the patient population and does not limit the claimed treatment to restoration or protection of only those bacterial families. Accordingly, the claims continue to encompass treatment across multiple distinct etiologies and patient populations.
Applicant argues that the application provides direct experimental support for the claimed bacteria because in vitro data demonstrate Reg3a promotes growth and survival of Faecalibacterium prausnitzii and Roseburia intestinalis under oxygen exposure.
Applicant’s arguments have been fully considered but not found persuasive. While the specification provides working examples demonstrating effects on F. prausnitzii and R. Intestinalis under specific experimental conditions, the claims are not limited to those organisms or those experimental conditions. Rather, the claims encompass treatment of gut microbiota imbalance resulting from multiple distinct etiologies. The specification does not provide representative working examples or predictive guidance demonstrating that the claimed therapeutic methods is enabled throughout the full scope of the amended claims without undue experimentation.
Applicant argues that the in vivo data show enrichment of Clostridiales, including Ruminococcaceae and Lachnospiraceae, in Reg3a-transgenic models.
Applicant’s arguments have been fully considered but not found persuasive. Evidence of enrichment of certain bacterial families in a particular transgenic model does not establish enablement of the full scope of the claimed therapeutic methods. The claims encompass treatment of gut microbiota imbalance arising from multiple unrelated causes in any host meeting the recited microbiota characteristic. The specification does not demonstrated that the observed effects extend across the full range of claimed etiologies or patient populations.
Applicant argues that the specification links these bacteria to anti-inflammatory effects and gut barrier improvement.
Applicant’s arguments have been fully considered but not found persuasive. While the specification may associate certain bacterial taxa with anti-inflammatory effects or gut barrier function, such disclosures do not demonstrate that administering Reg3a enables treatment of gut microbiota imbalance across the full scope of the amended claims. Correlation between bacterial abundance and physiological benefit does not substitute for representative enablement of the claimed therapeutic methods.
Applicants argue that the amended claims are now commensurate with the experimental evidence and supported across their full scope without undue burden.
Applicant’s arguments have been fully considered but not found persuasive. The relevant inquiry under 35 U.S.C. 112(a) is whether the specification enables the full scope of the claimed invention without undue experimentation. Although the amendments narrow one aspect of the claims, the claims remain directed to treating gut microbiota imbalance generally across multiple unrelated etiologies. The specification provides experimental data in limited disease models and for selected bacterial organisms but does not provide representative working examples or predictive guidance sufficient to enable treatment across the full scope of the amended claims without undue experimentation.
New Objections
Claims 1 and 11 are objected to for the following informality: it is suggested that the limitation of “decreased proportion of immune protective gram positive bacteria selected from the group consisting of bacteria of the…” be replaced with -decreased proportion of immune protective gram positive bacteria belonging to the Ruminococcaceae family and/or the Lachnospiraceae family..-
New Rejection
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 17-18 is 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 17 is rejected under 35 U.S.C. § 112(b) because it is unclear what subject matter is encompassed by the phrase “belongs to Faecalibacterium prausnitzii, and/or to the Lachnospiraceae family.” In view of the dependency from claim 9, which limits the bacteria to the Ruminococcaceae family, it is unclear whether claim 17 is intended to further limit the protected bacteria to Faecalibacterium prausnitzii, to alternatively encompass bacteria belonging to the Lachnospiraceae family, or both. Accordingly, the metes and bounds of claim 17 cannot be determined with reasonable certainty.
Claim 18 depends on claim 9, which limits the protected oxygen sensitive gram positive bacteria to those belonging to the Ruminococcaceae family. However, claim 18 further claims that the bacteria is Rosburia intestinalis. As drafted, the claim is internally inconsistent because Roseburia intestinalis does not belong to the Ruminococcaceae family. Therefore, it is unclear what subject matter claim 18 is intended to encompass.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Primary Examiner, Art Unit 1654
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