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 .
Claim Status
Pending claims 1‐20 have been examined on the merits.
Withdrawn Rejections
The rejection of claims 13 under 35 U.S.C. 112(b) is withdrawn in view of the claim amendment.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in
37 CFR 1.17(e), was filed in this application after final rejection. Since this application is
eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e)
has been timely paid, the finality of the previous Office action has been withdrawn pursuant to
37 CFR 1.114. Applicant's submission filed on 10/26/2025 has been entered.
Claim Rejections - 35 USC § 112 (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.
Claim 1-20 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 with respect to the
added language of “who does not exhibit gut microbial changes”. 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 claim recites “who does not exhibit gut microbial changes,” in a subject who is at risk of increased intestinal permeability. The specification (page 2-5) describes prevention and/or treatment of synucleinopathies, in subjects at risk of increased intestinal permeability, including patients with gut inflammation, constipation, gastroparesis, and any substances that induce intestinal permeability. The specification, however, does not explicitly teach, suggest, or even disclose a patient subgroup “who does not exhibit gut microbial changes.” The specification does not even disclose patients being selected because they lack gut microbial changes, or excluding patients from treatment who exhibit gut microbial changes. Furthermore, the specification does not describe or imply restricting administration of rebamipide to a subpopulation defined by the absence of gut microbial changes. To the contrary, the specification positively includes gut microbial alteration (e.g., dysmicrobia) or intestinal permeability, as part of the relevant patient population (page 5-6) to be treated with rabamipide. Therefore, given that the specification neither mention the absence of gut microbial changes nor distinguishes patients based on the presence or absence of such changes, for this reason, the added claim limitation clearly lacks adequate written description support.
Therefore, the specification fails to demonstrate possession of the claimed invention of “who does not exhibit gut microbial changes”. This is because the specification does not describe or disclose a patient subgroup “who does not exhibit gut microbial changes.”
Maintained Rejection with changes per claim Amendment
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1- 6, 8- 12, 14- 17- 20 are rejected under 35 U.S.C. 103 as being unpatentable over Niwa Y et al. J Gastroenterol. 2008;43(4):270-6 (“Niwa”) in view of Perez-Pardo et al. Curr Behav Neurosci Rep. 2017;4(4):361-368 (“Pardo”).
Regarding claim 1, Niwa at page 270 teaches rebamipide is effective in preventing NSAID-induced small-intestinal mucosal injuries in healthy subjects. Niwa at page 270 also teaches that NSAID can lead to increased intestinal permeability and inflammation. Given this association, one of ordinary skill in the art would recognize that rebamipide’s protection against mucosal injuries would also help mitigate an increased risk of intestinal permeability induced by NSAIDs.
Niwa does not explicitly teach preventing or treating synucleinopathy.
However, Pardo at page 362 teaches that intestinal permeability can contribute to synucleinopathy because of the deposition of alpha-synuclein protein in the enteric nervous system, which is a key feature of synucleinopathy, a type of Parkinson’s disease. Therefore, it would have been obvious to one of ordinary skill in the art (POSITA) to combine the teachings of Niwa and Padro to treat a patient with rebamipide to decrease risk of intestinal permeability and synocleinopaty, to arrive at the claim invention.
Regarding who does not exhibit gut microbial changes, the combined teaching of Niwa and Pardo describe NSAID damage the intestinal mucosa, increase gut permeability, and thereby lead to microbiota changes. However, rebamipide prevents NSAID-induced intestinal permeability or synucleinopathy progression, thus, a POSITA would find it obvious to administer rebamipide as prophylactic to at risk subjects to prevent microbiota changes. Thus, patients receiving such prophylaxis before microbiota alteration develop inherently correspond to the claimed subgroup “who does not exhibit gut microbial changes,” at the time of treatment, because such patients do not experience permeability or microbial changes.
Regarding claim 2, Niwa does not explicitly teach rebamipide is provided for prevention of a synucleinopathy. As applied to claim 1 above, since intestinal permeability can lead to synucleinopathy, it would have been obvious to one of ordinary skill in the art to use rebamipide to prevent intestinal permeability, in return, reduce the risk of synucleinopaty.
Regarding claim 3 and 17, Niwa does not explicitly teach person suffering from at least one condition selected from low grade inflammation of the gut wall, chronic constipation or gastroparesis. Pardo at page 362 teaches that patients with Parkinson disease can suffer from chronic constipation along side intestinal permeability. Therefore, it is obvious to one of ordinary skill in the art to expect certain population with intestinal permeability to also experience chronic constipation.
Regarding claim 4 and 18, Niwa does not explicitly teach that a person at risk of increased intestinal permeability is a person suffering from stress, imbalanced diet, bacterial, viral or parasitic infection. Padro at page 363 teaches that bacterial infection, such as small intestinal bacterial overgrowth (SIBO), can lead to increased intestinal permeability. Therefore, it is obvious to one of ordinary skill in the art to expect certain population with bacterial infection to be at risk of intestinal permeability.
Regarding claim 5- 6 and 19, Niwa does not explicitly teach that a person is at risk of increased intestinal permeability if exposed to non-steroidal anti-inflammatory drugs, alcohol, nicotine, food additives, chemotherapeutics and antibiotics. Niwa at page 270- 271 teaches NSAID can lead to small intestinal injury which can cause intestinal permeability. Niwa also teaches at page 270- 271 that patients were administered rebamipide plus diclofenac, an NSAID, with the goal of assessing the prevention of NSAID-induced-small-intestinal injuries.
Regarding claim 8 and 20, Niwa does not explicitly teach at risk of increased intestinal permeability is a person suffering from radiation therapy, chemotherapy, infectious or postinfectious impairment of the GIT mucosa, dysmicrobia, as an example.
Padro at page 363 teaches that individuals at risk for intestinal permeability may experience infectious or post-infectious damage to the gastrointestinal mucosa, as compromised gut barrier can lead to bacterial translocation and inflammatory products like lipopolysaccharides.
Regarding claim 9 and 10, Niwa does not explicitly teach that synucleinopathy is a form of Parkinson's disease. Padro at page 361- 363 discloses that synocleinopathy is associated with Parkinson’s disease.
Regarding claim 11 and 12, Niwa does not explicitly teach that a person is essentially without motor symptoms of the synucleinopathy and/or is essentially without alpha-synuclein aggregates in the cerebrospinal fluid.
Padro at page 362 and 363 teaches that gastrointestinal dysfunction, such as increased intestinal permeability, often precede motor symptoms in Parkinson’s disease. This indicates that gut health alterations can occur early in the disease, allowing for alpha-synuclein accumulation in the central nervous system without presenting as detectable motor symptoms. Therefore, one of ordinary skill in the art would infer individuals with intestinal permeability might not yet show significant clinical symptoms or may have reduced alpha-synuclein aggregates in the CSF.
Regarding claim 14, Niwa does not explicitly teach rebamipide is in an enteric sustained release or enteric controlled release. Enteric release formulations are well-established in the pharmaceutical industry for improving intestinal absorption and reducing gastrointestinal side effects. Therefore, it is obvious for one of ordinary skill in the art to consider an enteric release option as an extension of the table form.
Regarding claim 15 and 16, Niwa at page 271 teaches that rebamipide was administered at 300 mg daily for 1 week. Niwa does not explicitly teach pharmaceutically acceptable excipient
However, it would have been obvious to one of ordinary skill in the art to recognize that tablets typically contain excipients such as binders, fillers and glidants. These components are standard in tablet formulation to ensure proper tablet formulation, stability, uniformity and manufacturability. Therefore, it is obvious for one of ordinary skill in the art to expect rebamipide tablet to contain excipients such as binders, fillers and glidants.
Claims 7 is rejected under 35 U.S.C. 103 as being unpatentable over Niwa and Pardo as applied to claim 1 above, and further view of Leclercq et al. Transl Psychiatry. 2017 Feb 28;7(2):e1048 (“Leclerq”).
The combined teachings of Niwa and Pardo disclose the use of rebamipide to prevent synucleinopathy in subjects at risk of increased intestinal permeability.
However, the combined teachings of Niwa and Pardo do not explicitly teach rebamipide is administered to a person abusing alcohol, nicotine or another drug.
Leclerq at page 1 and 2 teaches that alcohol abuse could lead to increased intestinal permeability. Therefore, given that Niwa at page 270- 271 teaches rebamipide can decrease the risk of intestinal permeability, which may also prevent synycleinopathy. Thus, it is obvious to one of ordinary skill in the art to use rebamipide as preventive measure for an individual who abuses alcohol.
Claims 13 is rejected under 35 U.S.C. 103 as being unpatentable over Niwa and Pardo as applied to claim 1 above, and further view of Rebamipide. (2002). fda.gov. Retrieved September 26, 2024, from https://verification.fda.gov.ph/files/DRP-6291_PI_01.pdf (“Reb”)
Regarding claim 13, Niwa at page 271 teaches that rebamipide was administered at 300 mg daily for 1 week. However, Niwa does not explicitly teach the dosage form for rebamipide.
Reb page 1 teaches that rebamipide is available as both a standard tablet and a film-coated tablet. Therefore, it would be obvious for one of ordinary skill in the art to select a formulation for rebamipide that conforms to common practices in gastroenterology, such as utilizing a tablet dosage form.
Response to Argument
Applicant argues that Niwa does not explicitly teach rebamipide can have any effects on intestinal permeability. Applicant's argument is not persuasive, because Niwa teaches rebamipide is effective in preventing NSAID-induced small-intestinal mucosal injuries in healthy subjects. Thus, a person of ordinary skill in the art (POSITA) would understand that preventing such injuries necessarily implies that the treatment is effective to the underlying condition, including intestinal permeability, regardless of whether the term is explicitly used.
Applicant argues that Niwa does not teach any relationship between rabamipide and α-synuclein aggregation and synucleinopathy progression. Applicant’s argument is not persuasive because the 103 rejection is based on a combined teaching of Niwa and Pardo. For example, while Niwa does not explicitly α-synuclein aggregation and synucleinopathy progression, but Niwa teaches relationship between rebamipide and intestinal permeability. Pardo, however, teaches intestinal permeability contributes to synucleinopathy and α-synuclein pathology. Thus, the combined teaching of Niwa and Pardo establish a clear link between rebamipide and prevention of synucleinopathy progression via intestinal permeability.
Applicant also argues that Niwa’s teaching is limited to diclorfenac-induced injury only, and therefore contradicts any assumption that chronic intestinal permeability was present. However, Applicant's argument is not persuasive, because Niwa’s clinical study demonstrate that, even in healthy patients, diclofenac regimen can induce intestinal mucosal injury, and that rebamipide significantly prevents mucosal injuries by restoring barrier integrity. Furthermore, Niwa does not disclaim or exclude chronic or ongoing permeability changes, but in fact the evaluation of injury prevention over multiple treatment periods supports the existence of a sustained barrier defect due to chronic exposure to NSAID. Thus, Applicant improperly narrows Niwa’s teachings, which reasonably encompass chronic intestinal permeability because of the sustained exposure to NSAID by chronic NSAID users.
Applicant argues that Pardo merely summarizes the gut-brain hypothesis and does not establish a direct link between intestinal permeability and Parkinson’s disease (PD). Applicant’s argument is not persuasive because Pardo repeatedly reports that PD patients exhibit increased intestinal permeability that correlates with enteric α-synuclein aggregation and disease progression. Although Pardo notes that permeability has not yet been shown to precedes PD in healthy patients, Pardo nonetheless identifies intestinal barrier dysfunction as a mechanical relevant contributor to PD pathology via gut-brain axis, therefore clearly establishing a relationship between intestinal permeability and PD. Therefore, the combined teaching of Niwa and Pardo establish the use of rebamipide to prevent intestinal permeability without hindsight. Thus, a POSITA would find it obvious to use rebamipide prophylactically to mitigate downstream synuclein pathology and PD progression.
Unexpected Technical Effect
Applicant argues that administration of rebamipide leads to a decreased of α-synuclein aggregation, and the in vivo data disclose an unexpected mechanism of action that is neither suggested nor disclosed by Niwa and Pardo. It is important to highlight, that the claimed invention is directed to a method of treatment or prevention, not a mechanism of action. The combined teaching of Niwa and Pardo establish NSAID-induced small-intestinal mucosal injuries in healthy subjects and rebamipide reverses the damage by restoring barrier integrity of the intestine. Given obviousness under 103 focuses on the claimed method and its therapeutic effect, unexpected results based solely on a new or previously unknown mechanism do not negate the obviousness of using the same active ingredient in the same context. Therefore, the argument of unexpected mechanism of action does not justify withdrawal of the 103 rejection or issuance of a notice of allowance.
Distinct patient group
Applicant’s argument that the claimed method targets a “distinct patient population” is not persuasive. The specification provides no disclosure or suggestion of a subgroup defined by the absence of the gut microbial changes. As explained in the 103 rejection above, the combined teaching of Niwa and Pardo teach prophylactic rebamipide administration to patients at risk of increased intestinal permeability, which inherently encompasses patients treated prior to the development of microbiota changes. Thus, Applicant’s assertation of “distinct population” is speculative, unsupported by the specification.
Conclusion
Therefore, claims 1-20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622