DETAILED ACTION
Status of Claims
Claims 1-13 and 16-20 are pending and under consideration.
Claim 14-15 are cancelled.
Claims 1-6, 8-10, 13, 17, 19, and 20 are amended.
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 .
Priority
This application is a 371 National Phase Application of PCT/EP2020/074494 filed September 2, 2020, which claims the benefit of priority to European Patent Application No. EP19020505.4, filed on September 3, 2019.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d), and the certified copy has been filed.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
In nonprovisional applications, applicants and other individuals substantively involved with the preparation and/or prosecution of the application have a duty to submit to the Office information which is material to patentability as defined in 37 CFR 1.56. The provisions of 37 CFR 1.97 and 37 CFR 1.98 provide a mechanism by which patent applicants may comply with the duty of disclosure provided in 37 CFR 1.56 using an IDS. The IDS may be filed using form PTO/SB/08. See MPEP § 609.
37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. The applicant is again reminded of their legal obligation to submit to the Office information which is material to patentability.
WITHDRAWN OBJECTIONS
The examiner withdraws objections to claim 9 based on revisions completed by Applicant.
WITHDRAWN REJECTIONS
The examiner withdraws rejections to Claim 14-15 under 35 U.S.C. 112(a), 35 U.S.C. 102(a)(1) and(a)(2) as claims were cancelled by Applicant.
The examiner withdraws rejections to claims 1-20 under 35 U.S.C. 112(b) based on amendments to the claims and cancellation of claims 14-15 by Applicant.
NEW OBJECTIONS
New Matter
The amendment filed June 12, 2025 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: Applicant amended the specification to change the definition of Rebamipide as explained in Applicant’s Remarks: "Rebamipide", as used herein, shall include all forms of this active ingredient, i.e. the anhydrous form, hydrated or solvated form (e.g. hemihydrate form), crystalline forms; and pharmaceutically acceptable salts thereof (page 3, lines 10-14). However, prodrugs of rebamipide are not intended to be covered. In order to improve the interpretation of the claims, the scope of the claims has been limited to rebamipide or a pharmaceutically acceptable salt thereof. The description has been amended accordingly.”
As aforementioned, the amendment has not been entered as it constitutes new matter. The original definition of “Rebamipide” is maintained as explained in the Claim Interpretation section.
The examiner suggests Applicant instead amend the instant claims to limit the definition of “rebamipide,” to reflect the metes and bounds of patent protection sought.
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Interpretation
As defined by Applicant, “"Rebamipide", as used herein, shall include all forms of this active ingredient, such as the anhydrous form, hydrated or solvated form (e.g. hemihydrate form), crystalline forms; and pharmaceutically acceptable salts thereof (page 3, lines 10-14).
Consequently, using broadest reasonable interpretation, rebamipide is interpreted to additionally include all prodrugs of rebamipide.
As defined by Applicant, “Cancer" as used herein is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. This invention relates specifically to cancers associated with increased intestinal permeability, a condition that enables passage of carcinogens present in the gastrointestinal tract into the body proper, thus contributing to development of malignancies. These carcinogens may trigger cancerous growth directly in the bowel and/or surrounding tissues but also in more distant organs and tissues. The underlying mechanism for this phenomena resides in the ability of carcinogens to spread via bloodstream even to remote parts of the body.”
As defined by Applicant, “Increased intestinal permeability" is used herein as a term designating little intestinal wall defects, including those caused by subclinical chronic inflammation (low grade inflammation) of the gut wall. These intestinal wall defects may be manifested e.g. by chronic constipation or gastroparesis. Increased intestinal permeability may be diagnosed using specific tests, such as lactulose-mannitol test (LAMA test; e.g., Sequeira J.R. et al. (2014) PLoS One; 9(6):e99256), A-1-AT test, or zonulin test. Typically, increased intestinal permeability is permeability of the intestinal wall to particles having the size of more than 4 Angstroms in radius.”
As defined by applicant, “The term “abuse" as used herein is meant to include any consumption, which is not necessary for medical reasons and leads to dependency and/or health impairments including low grade inflammation of the gut wall.”
As defined by applicant “Prophylaxis" or “prophylactic use" shall be understood herein as preventing or delaying the onset of the disease including its recurrence in patients with complete or partial remission, e.g. after surgical treatment, chemotherapy, radiation therapy, or immunotherapy. It is also intended to include preventing or delaying the progression of the disease. In such a case rebamipide is administered to a patient who is in an initial or early stage of the disease to be treated in order to prevent or delay its progression to the next stage. The prophylactic effect of rebamipide resides in its ability to prevent passage of carcinogenic substances and other toxins into the body proper, thereby preventing events triggering cancer initiation.”
As defined by Applicant, “Treatment" shall be understood herein as a therapy that is able to slow, stop, inhibit or reverse the disease. It is also meant to cover reduction or alleviation of clinical symptoms of the disease. “Slowing down" the disease means reducing its progress while not being able to completely stop or reverse it, whereas “stopping" the disease means being able to completely halt its progression.
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 112(a)
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 1-13 and 16-20 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating and preventing some types of cancer (i.e.: gastric and colorectal) and some patient populations (i.e.: mice), does not reasonably provide enablement for preventing all types of cancer claimed and all types of patient populations claimed.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP 2164.01 (a).
Upon consideration of the factors discussed below, the examiner concludes that one skilled in the art could not practice the invention without being burdened with undue experimentation based on the information provided by the applicant.
A discussion of these factors they relate to the pending claims follows.
Breadth of Claims
Amended claim 1 is directed to “a method preventing cancer in a human subject having increased intestinal permeability or being at risk thereof comprising suffering from increased intestinal permeability comprising administering to the subject an effective amount of rebamipide or a pharmaceutically acceptable salt thereof , wherein said cancer is associated with increased translocation of carcinogens due to compromised intestinal barrier function and wherein said administration reduces intestinal permeability.”
Applicant defines prophylaxis as “as preventing or delaying the onset of the disease including its recurrence in patients with complete or partial remission, e.g. after surgical treatment, chemotherapy, radiation therapy, or immunotherapy. It is also intended to include preventing or delaying the progression of the disease.”
Applicant also defines treatment as “a therapy that is able to slow, stop, inhibit or reverse the disease. It is also meant to cover reduction or alleviation of clinical symptoms of the disease. Slowing down" the disease means reducing its progress while not being able to completely stop or reverse it, whereas, stopping" the disease means being able to completely halt its progression.”
Claims 4-5 recite a diversity of cancers that range from B-cell lymphoma to pancreatic cancer to breast cancer.
Cancer is a broad class of heterogenous diseases for which there exists no general treatment or prevention. Hanahan explains that “there are more than 100 distinct types of cancer, and subtypes of tumors can be found within specific organs” (Hanahan, Douglas, and Robert A. Weinberg. "The Hallmarks of Cancer." Cell 100, no. 1 (2000): 57-70).
Claim 5 is directed to “wherein the person at risk of increased permeability is a person suffering from stress, imbalanced diet, etc.” Applicant has provided no criteria to evaluate stress levels or what constitutes an imbalanced diet; therefore, a person of ordinary skill in the art would interpret such limitations to broadly include all humans.
Consequently, it is reasonable to conclude that the claims are broad with respect to the patient population, disease, and goals of prevention.
The nature of the invention
The nature of the invention is methods to treat or prevent cancer in a person suffering from increased intestinal permeability or in a person who is at risk of increased intestinal permeability.
The state of the prior art
The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). See Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021).
The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification. See MPEP § 2164.05 (a).
To the best knowledge of the examiner, there is no pharmacological agent know to prevent all types of cancer.
Additionally, to date, there are no pharmacological agents and/or methods known to specifically prevent all of the cancer types recited in claims 4-5 and 11-12.
Furthermore, the correlations between diet and cancer are still not well-established and consistent in the art, require long-term studies, and face challenges addressing heterogeneity of populations, diet, cancer and tumor types.
Mayne explains that “Despite the potentially important roles of diet and nutrition in cancer prevention, the evidence to support these roles is widely perceived by the public and health professionals as being inconsistent. Nutritional and dietary patterns are complex; therefore, the use of a reductionist approach to investigations, by focusing on specific nutrients, can produce misleading information.
“The currently available dietary-assessment approaches have been sufficiently informative to identify many important diet–cancer and other diet–disease associations; however, other relationships might have been obscured, as a consequence of various design challenges. For example, dietary exposures across the life-course (in utero, childhood, adolescence, and so on) could potentially be of great relevance, but there is a dearth of literature on this subject. Even the best measurement tools, together with the use of objective biomarkers, will not be informative if the exposure is measured at the wrong time point. In addition, cancers typically develop over decades before diagnosis, necessitating studies with long follow-up durations to capture cases and enable identification of dietary associations; indeed, inconsistent findings for some diet–cancer associations might be a consequence of the very long latency for cancer development.”
The biology of cancers arising within and across different organ sites is known to be heterogeneous, and this variability is another issue that affects the interpretation of research on the role of dietary factors in cancer risk and disease progression. A clinically-detected cancer can arise via a number of carcinogenesis pathways, through various genetic mutations; therefore, tumours originating within the same organ site are often aetiologically very different.”
“Another example of the heterogeneity in diet–cancer associations according to cancer subtype comes from patients with breast cancer. Research has revealed up to 21 distinct subtypes of breast cancer with different risk factors, aetiologies, and outcomes; dietary associations also vary by tumour subtype. For example, in the large, long-term Pooling Project of Prospective Studies of Diet and Cancer, a protective effect of fruit and vegetable intake on oestrogen receptor (ER)-negative breast cancer, but not on ER-positive breast cancer, was consistently demonstrated across 20 studies. Thus, the somewhat different conclusions as to the role of various nutritional factors in disease aetiology, based on data from earlier studies that failed to account for differences by histology, are perhaps not surprising (Mayne, Susan T., Mary C. Playdon, and Cheryl L. Rock. "Diet, nutrition, and cancer: past, present and future." Nature reviews clinical oncology 13, no. 8 (2016): 504-515).”
In addition to the unpredictability pertaining to diet and cancer, there is also a lack of clinical studies on the use of rebamipide as an anti-cancer drug. Rebamipide is well-known in the art as a gastroprotective agent and for treating gastric ulcers.
(Tanigawa, Tetsuya, Rama Pai, Tetsuo Arakawa, and Andrzej S. Tarnawski. "Rebamipide inhibits gastric cancer cell growth." Digestive diseases and sciences 52 (2007): 240-247 and Murai, R., T. Kanbe, T. Mukoyama, T. Shimomura, K. Hashiguchi, Y. Yoshida, H. Tsuchiya, Y. Hoshikawa, A. Kurimasa, and G. Shiota. "Effect of rectal administration of rebamipide on dextran sulfate sodium-induced colitis: role of hepatocyte growth factor." Inflammation Research 56 (2007): 240-245).
To the best of the examiner’s knowledge, there are no reports of anti-cancer effects for rebamipide for the various other cancers recited in claims 4-5 and 11. There are also no accounts of rebamipide used routinely in patient populations either as a prophylactic or treatment for any cancer. Many cases have focused on inducing cancer in murine models; however, there exists little experimental support screening any actual human cancer cells lines or performing standard in vivo studies to model the human cancers as claimed in instant invention.
The level of one of ordinary skill
The person of ordinary skill in the art is a hypothetical person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the level of ordinary skill in the art may include: (A) "type of problems encountered in the art;" (B) "prior art solutions to those problems;" (C) "rapidity with which innovations are made;" (D) "sophistication of the technology; and" (E) "educational level of active workers in the field. In a given case, every factor may not be present, and one or more factors may predominate." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP § 2141.03 (I)
The invention described pertains to medicine and pharmacology. One of ordinary skill would be a person with training in oncology, pharmacology, biochemistry or a related technical discipline.
The level of predictability in the art
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling.
The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. See MPEP § 2164.03.
Consequently, technologies involving physiological activity as opposed to mechanical or electrical inventions are generally regarded as being unpredictable sciences.
As aforementioned, cancer, including the specific cancer types recited in instant application is an unpredictable, complex and heterogenous disease. Causes of cancer are equally unreliable and can originate from diet, genetics, environment and a combination of factors which are not easily predicted.
Additionally, the correlation between diet and cancer is also known to be unpredictable and highly variable based on patient population, diet and other factors.
Based on these culminative factors, it is reasonable to conclude that predictability in the art is extremely low.
Consequently, the applicant would need to provide more details, working examples and guidance in order for the claimed invention to be enabling based on the scope and nature of the claimed invention.
The amount of direction provided by the inventor
As aforementioned, the amount of direction provided depends on the prior art and predictability of in the art. Based on the scope of protection sought by the applicant and the discussion aforementioned, the inventor has failed to provide sufficient direction for one ordinarily skilled in the art to practice the disclosed invention as claimed.
The existence of working examples
Applicant provided the following working examples:
• In vivo studies using a DSS model in mice to induce increased intestinal permeability and administration of PhIP (a compound found in red meat that is an alleged carcinogen) centered around studying colon cancer.
Applicant has provided no experimental data for the in vivo studies claimed to have been performed. Page 11 of Applicant’s specification lists various parameters claimed to have been observed; however, there is no actual data provided.
Although Applicant demonstrates that administering a specific chemical compound to mice causes colon tumors and rebamipide administration reduced tumor size, this does not mean that the claimed invention is enabled for preventing and treating cancer in a person.
Applicant has provided no support for any additional cancers recited in claims 4-5 and 11-12. Applicant has provided no support for the various risk factors recited in claims 5-6 and 8-10.
Applicant has provided no support for the elements of claim 7 involving combination therapies. Applicant has presented no studies exploring patient populations, patient populations at risk, and patients at various stages of cancer.
There is no mention of details identifying a population of subjects at risk or in need thereof, which would appear to include all populations. There is also no mention of populations that are at higher risk than others or any guidance for one in the art to identify who is at risk.
Applicant has performed no studies encompassing the wide range of cancer types listed within the claims, no studies encompassing the broad scope pertaining to subject, and no population studies for populations at risk for the conditions listed.
A working example is based on work actually performed. See MPEP § 2164.02
The issue of "correlation" is related to the issue of the presence or absence of working examples. "Correlation" as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a "working example" if that example "correlates" with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute "working examples." See MPEP § 2164.02, II.
On this basis and the prior discussion, the working examples do not meet the requirements for using the claimed invention and are not enabling with respect to the scope of the claims for the reasons aforementioned.
One ordinarily skilled in the art would be met with undue experimentation in order to practice the invention as claimed based on the sparse experimental details, guidance and support for a working invention based on the scope of patent protection sought by Applicant.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed, the quantity of experimentation depends on the prior art, the predictability of the art, and the direction provided by the inventor.
In order for one ordinarily skilled in the art to practice the invention as disclosed, one would require but are not limited to the following:
In vivo and/or in vitro studies used to actually demonstrate any effects on treating and preventing the wide range of cancers covered within the scope of the instant claims.
Clinical studies in patient populations for cancers where murine models are known to not translate into the clinical setting.
Studies studying the patient populations at risk based on various risk factors (i.e.: stress, diet, drug abuse, etc.).
Methods for identifying a population of subjects at risk and guidance for determining such populations.
Methods to determine if a subject will develop or not develop cancer based on using the claimed invention and the risk factors recited in the instant claims.
Experiments to determine effective dose, timing, and a treatment plan for the cancers claimed encompassing disease progression.
Long-term studies to confirm no recurrence, particularly based on the prevalence of dormancy in different cancers such as breast cancer, which can lead to recurrence after decades.
Based on weighting the evidence, the examiner concludes that one ordinarily skilled in the art would require undue experimentation in order to practice invention based on the sparse details provided and scope of invention defined in Claim 1-20.
Consequently, claims 1-20 remain rejected in accordance with 112(a) for not reasonably enabled for all types of cancer claimed, all types of patient populations claimed and prevention for all types of cancer claimed. This is a scope of enablement rejection.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 16-20 remain rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Cho et al (USPN 11,420,963 B2) (herein referred to as Cho).
Regarding claim 1, Cho teaches “a method of prophylaxis and/or treatment of cancer in a person suffering from increased intestinal permeability or in a person who is at risk of increased intestinal permeability comprising providing rebamipide prodrug to the person (Abstract).”
Specifically, Cho teaches that “in addition to gastric ulcer, acute gastritis and chronic gastritis, rebamipide is known to have prophylactic and therapeutic effects on xerophthalmia, cancer, osteoarthritis, and rheumatoid arthritis (Column 1, last paragraph, lines 60-67).”
Cho also recites a method for treating a disease including cancer using rebamipide (column 146, claim 9 of Cho).
Regarding Claim 16, Cho teaches “wherein rebamipide is administered in an oral pharmaceutical form (column 18, paragraphs 2-3 at lines 12-28)
Regarding claim 17, Cho teaches “wherein the oral pharmaceutical form is a form with enteric release (column 18, paragraph 2 at lines 13-16).”
Specifically, Cho teaches that “the pharmaceutical composition of the present invention may be formulated into a preparation suitable for use in releasing the active ingredient in an immediate, sustained or delayed manner. The preparation may be in such a form as a powder, a granule, a tablet, an emulsion, a syrup, an aerosol, a soft or hard gelatin capsule, a sterile injection, or a sterile powder (column 18, paragraph 2 at lines 13-16).”
Regarding claim 18, Cho teaches “wherein the pharmaceutical form contains rebamipide and at least one pharmaceutically acceptable excipient (column 18, paragraph 1, lines 3-5).”
Specifically, Cho teaches “In addition, the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive. The additive may be any one of a carrier, an excipient, and a diluent, as typified by lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. A filler, an anti-coagulant, a lubricant, a humectants, a flavoring agent, an emulsifier, and a preservative may be used in the pharmaceutical composition of the present invention (column 18, paragraph 1, lines 3-12).” Therefore, Cho teaches that the pharmaceutical additive may be a pharmaceutically acceptable excipient.
Regarding claims 19-20, Cho teaches “wherein rebamipide is administered in a daily dose of 1 to 5000 mg (column 17, lines 56-67).”
Specifically, Cho teaches “The pharmaceutically effective daily dosage is about 0.5 mg/kg body weight to 100 mg/kg body, and preferably about 1 mg/kg body weight to 30 mg/kg body weight of the rebamipide or its pharmaceutically acceptable salt thereof. However, the pharmaceutically effective dose may vary depending on various factors including the severity of disease, the patient's age, weight, health condition, and sex, the route of administration, and the time of administration (column 17, lines 56-67).
Although technically Cho’s invention pertains to rebamipide prodrug, Applicant defines on page 3, lines 10-14 of the specification, that “"Rebamipide", as used herein, shall include all forms of this active ingredient, such as anhydrous form, hydrated or solvated form (e.g. hemihydrate form), crystalline forms; and pharmaceutically acceptable salts thereof.”
Consequently, Applicant’s definition is inclusive of any rebamipide prodrugs, such as those claimed by Cho.
Claim 1-2, 4-5, and 13 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Tanigawa et al (Tanigawa, Tetsuya, Rama Pai, Tetsuo Arakawa, and Andrzej S. Tarnawski. "Rebamipide inhibits gastric cancer cell growth." Digestive diseases and sciences 52 (2007): 240-247) (herein referred to as Tanigawa).
Regarding claims 1-2 and 4, Tanigawa teaches “a method preventing cancer in a human subject having increased intestinal permeability or being at risk thereof comprising suffering from increased intestinal permeability comprising administering to the subject an effective amount of rebamipide or a pharmaceutically acceptable salt thereof , wherein said cancer is associated with increased translocation of carcinogens due to compromised intestinal barrier function and wherein said administration reduces intestinal permeability,” “wherein the cancer is caused by carcinogens present in food,” and the cancer is “gastric cancer.”
The examiner notes the ambiguity in determining whether the cancer is caused by carcinogens present in food, and as explained in the new rejections section, for the purposes of examination is interpreting “cancer caused by carcinogens present in food” to refer to the cancers recited in claims 3-4.
Additionally, as per MPEP 2131.02 “A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus. In re Slayter, 276 F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960); In re Gosteli, 872 F.2d 1008, 10 USPQ2d 1614 (Fed. Cir. 1989),” and Tanigawa teaches a species falling within the claimed genus (i.e.: gastric cancer).
Specifically, Tanigawa teaches rebamipide inhibits human gastric cancer cell proliferation (Abstract).
Regarding claim 5, Tanigawa teaches the elements of claim 1 and “wherein the person at risk of increased intestinal is a person suffering from stress, imbalanced diet, bacterial, viral or parasitic infection.”
Specifically, it is well-known in the art and further elaborated by Tanigawa that “Gastric cancer is recognized as a multifactorial disease. Genetic factors, infection with Helicobacter pylori, environmental factors, and lifestyle factors, including dietary habit, are involved in the pathogenesis of gastric carcinogenesis (page 240, column 2, paragraph 2).”
Regarding claim 13, Tanigawa teaches the elements of claim 1 and “wherein the person is in complete or partial remission of cancer after previous treatment (page 242 column 2, paragraph 1 and Figure 1).”
Specifically, Tanigawa demonstrates that rebamipide suppresses gastric cancer cell proliferation up to 71% at 24 (page 242 column 2, paragraph 1 and Figure 1).
Regarding claim 15, Tanigawa also teaches “wherein rebamipide is used in prophylaxis of cancer (page 245, column 1, paragraph 2).”
Specifically, Tanigawa teaches the mechanism of inhibitory action for rebamipide involving Cdk inhibitors, which are targets for prevention and therapy for gastric cancer (page 245, column 1, paragraph 2).
Claim 1-3, and 10-12 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Murai et al. (Murai, R., T. Kanbe, T. Mukoyama, T. Shimomura, K. Hashiguchi, Y. Yoshida, H. Tsuchiya, Y. Hoshikawa, A. Kurimasa, and G. Shiota. "Effect of rectal administration of rebamipide on dextran sulfate sodium-induced colitis: role of hepatocyte growth factor." Inflammation Research 56 (2007): 240-245).
Regarding claims 1-3, 10, 11, 12 and 15, Murai teaches “a method of prophylaxis and/or treatment of cancer in a person suffering from increased intestinal permeability or in a person who is at risk of increased intestinal permeability comprising providing rebamipide to the person,” “wherein the cancer is caused by carcinogens present in food,” and the cancer is “colon cancer.”
Specifically, Murai teaches prophylactic effects of rebamipide for colorectal cancer, which is inclusive to colon cancer, “In IBD [inflammatory bowel disease], especially UC[ulcerative colitis], the repeated injury and repair may lead to an increase in the risk of colorectal cancer. Recently, HGF and c-Met was demonstrated to be highly expressed in the mucosa of UC and c-Met was increased in UC-associated colorectal cancer. These observations suggest that local expression of HGF may enhance the risk of colorectal cancer in the colonic mucosa of IBD via a cycle of repeated injury and repair. However, the blockade of this cycle by repair of colonic mucosa by rebamipide should reduce the genetic damage instead (page 244, column 2, paragraph 3).”
Regarding claims 10-12, Murai teaches the limitation “wherein the person suffering from increased intestinal permeability is a person suffering from chronic intestinal inflammation,” “wherein the cancer is colorectal cancer (page 244, column 2, paragraph 3).”
Inflammatory bowel disease (IBD) is known in the art to be characterized by chronic intestinal inflammation. As aforementioned, Murai’s studies on rebamipide are directed towards colorectal cancer prevention, specifically studying chronic intestinal inflammation due to the cycle of repeated injury and repair as is typical for IBD sufferers, which reads on claim 10-12.
Claim 1-2, 4, 6-7, 9, 16, and 18 are rejected under 35 U.S.C. 102(a)(1)(a)(2) as being anticipated by Yasuda et al. (Yasuda, Takashi, Hiroshige Chiba, Takafumi Satomi, Akira Matsuo, Tadayoshi Kaneko, Daichi Chikazu, and Hironobu Miyamatsu. "Preventive effect of rebamipide gargle on chemoradiotherpy-induced oral mucositis in patients with oral cancer: a pilot study." Journal of Oral & Maxillofacial Research 2, no. 4 (2012): e3.)
Regarding claims 1, 2,4, 6, and 7, Yasuda teaches “a method of prophylaxis and/or treatment of cancer in a person suffering from increased intestinal permeability or in a person who is at risk of increased intestinal permeability comprising providing rebamipide to the person,” “wherein the cancer is caused by carcinogens present in food,” and the cancer is “oral cavity cancer (Abstract).”
Specifically, Yasuda teaches that rebamipide is used in treating oral cancer, particularly in reducing the severity of mucositis (Abstract).
Regarding claims 6, 7, and 9, Yokota teaches “wherein the person at risk….is a person exposed to….chemotherapeutics, and “wherein rebamipide is co-administered…with chemotherapeutic,” and “wherein the person is exposed to….radiation therapy, chemotherapy.”
Specifically, Yasuda teaches administration of rebamipide with docetaxel and radiation therapy in treating oral cancer (page 2, column 2, paragraph 2).
Regarding claim 14, Yasuda teaches “wherein the person is in an initial or early stage of cancer.”
Specifically, Yasuda teaches a patient population at various cancer stages including initial or early-stage cancer (page 4, Table 2).
Regarding claims 16 and 18, Yasuda teaches “wherein rebamipide is administered in an oral pharmaceutical form,” “wherein the pharmaceutical form contains rebamipide and at least one pharmaceutically acceptable excipient selected from preservatives and solubilizers.”
Specifically, Yasuda teaches a rebamipide gargle solution containing additives that are preservatives and solubilizers (page 2, column 2, last paragraph; page 3, column 1, paragraph 1, and page 3, column 2, Table 1).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 6, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Tanigawa et al. (Tanigawa, Tetsuya, Rama Pai, Tetsuo Arakawa, and Andrzej S. Tarnawski. "Rebamipide inhibits gastric cancer cell growth." Digestive diseases and sciences 52 (2007): 240-247) (herein referred to as Tanigawa) in view of He et al. (He, Zheng, Ting-Ting Zhao, Hui-Mian Xu, Zhen-Ning Wang, Ying-Ying Xu, Yong-Xi Song, Zhong-Ran Ni et al. "Association between alcohol consumption and the risk of gastric cancer: a meta-analysis of prospective cohort studies." Oncotarget 8, no. 48 (2017): 84459) (herein referred to as He).
As aforementioned, Tanigawa teaches the elements of claim 1 for “a method of prophylaxis and/or treatment of cancer in a person suffering from increased intestinal permeability or in a person who is at risk of increased intestinal permeability comprising providing rebamipide to the person,” “wherein the cancer is caused by carcinogens present in food,” and the cancer is “gastric cancer”(Abstract).
Tanigawa does not teach the elements of claims 6 and 8 “wherein the person at risk of increased intestinal permeability is a person exposed to at least one substance selected from…alcohol,” and “wherein rebamipide is administered to a person abusing a drug.”
He discloses meta-analysis of studies to evaluate the association between alcohol consumption and the risk of gastric cancer, concluding that “heavy alcohol consumption significantly increased the risk of gastric cancer across all subgroups (page 84468, column 2, paragraph 4, lines 7-12).”
Therefore, it would have been prima facie obvious for an artisan in the field of pharmaceutical science before the effective filing date of the claimed invention to have modified
the methods taught by Tanigawa to treat gastric cancer using rebamipide to include patient populations exposed alcohol and patients that abuse alcohol because Tanigawa teaches that rebamipide has anti-proliferative properties against gastric cancer and because He teaches that heavy alcohol consumption significantly increases the risk of gastric cancer, suggesting such population would be an optimal target.
A person of ordinary skill in the art would be motivated to modify Tanigawa’s invention to include patients exposed to alcohol and alcohol abuse in treatments for gastric cancer using rebamipide because rebamipide is a mucosal protective agent used clinically for treating ulcers and suppresses cell proliferation of gastric cancer cells and because it is known that alcohol abusers have increased risks for developing gastric cancer and increased intestinal permeability and would therefore benefit from the pharmacological profile of rebamipide. Such modification would be obvious to try based on known risk factors for gastric cancer.
Therefore, by modifying Tanigawa’s invention to expand the patient population to target patients exposed to alcohol and alcohol abuse, one would have a reasonable expectation of success at arriving at the claimed invention as a highly predictable result.
NEW REJECTIONS
Applicant’s claim amendments have necessitated new grounds of rejection.
Claim Rejections - 35 USC § 112(b)
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 1-2, 5-11, 13, and 16-20 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.
The metes and bounds of claims 6 and 55 are rendered uncertain by the phrase “thereof , wherein said cancer is associated with increased translocation of carcinogens due to compromised intestinal barrier function” because it is unclear what cancers Applicant is intending to claim.
Dutta explains that “While increased translocation of intestinal luminal content is associated with carcinogenesis and poor therapeutic response, the cause-effect relationship is often bidirectional.”
Dutta further explains that “Disease and therapeutic interventions not only cause dysbiosis and gut permeability, they also affect microbiota and epithelial barrier integrity in other sites. Therefore, the synergistic effects of microbiome of different organs in immune function regulation/dysregulation and therapeutic outcomes should also be considered. In addition, cancer treatment strategies based on gut microbiota results in humanized mice models or mice with transplanted human tumors may not be directly translational and can be confounding. Transplanted tumors may also not possess all its original characteristics necessary to influence microbiome changes and elicit unfavorable immune responses [137]. Thus, without a more comprehensive understanding of the interplay between microbiota in different tissues, and the knowledge of how to modulate them for specific immune response, it would remain a challenge to formulate an optimal cancer therapeutic strategy (Dutta, D. and Lim, S.H., 2020. Bidirectional interaction between intestinal microbiome and cancer: opportunities for therapeutic interventions. Biomarker Research, 8(1), p.31).”
Likewise, the metes and bounds of claim 2 are rendered uncertain by the phrase “wherein the cancer is caused by carcinogens present in food” because it is unclear what cancers Applicant is intending to claim.
The National Research Council (US) Committee on Comparative Toxicity of Naturally Occurring Carcinogens explains that “Estimates of potential dietary cancer risks are subject to considerable uncertainty; for example, epidemiological studies have failed to provide unambiguous evidence of the effects of dietary fat on cancer risk. Estimates of potential cancer risks associated with low levels of individual food chemicals derived on the basis of laboratory results are highly uncertain. The application of animal cancer test data to humans requires extrapolation from the high doses used in laboratory studies to much lower doses corresponding to concentrations in the human diet, and extrapolation from animals to humans. The joint effects of ingestion of multiple agents in the form of complex dietary mixtures are also difficult to define. Consequently, in evaluating dietary cancer risks, it is important that both uncertainty and variability be recognized and, if possible, characterized (National Research Council (US) Committee on Comparative Toxicity of Naturally Occurring Carcinogens. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington (DC): National Academies Press (US); 1996. 5, Risk Comparisons. Available from: https://www.ncbi.nlm.nih.gov/books/NBK232623/).”
By example only, Handel et al discuss conflicting research on the role of processed meat consumption and the risk of cancer.
Handel states “In summary, there are severe methodological limitations to the majority of the previously published systematic reviews and meta-analyses that examined the consumption of processed meat and the risk of cancer. Many lacked the proper assessment of the methodological quality of the primary studies they included, or the literature searches did not fulfill the methodological standards needed in order to be systematic and transparent. The primary studies included in the reviews had a potential risk for the misclassification of exposure, a serious risk of bias due to confounding, a moderate to serious risk of bias due to missing data, and/or a moderate to serious risk of selection of the reported results. All these factors may have potentially led to the overestimation of the risk related to processed meat intake across all cancer outcomes. Thus, with the aim of lowering the risk of cancer, the recommendation to reduce the consumption of processed meat and meat products in the general population seems to be based on evidence that is not methodologically strong (abstract) (Händel, Mina Nicole, Jeanett Friis Rohde, Ramune Jacobsen, and Berit Lilienthal Heitmann. "Processed meat consumption and the risk of cancer: a critical evaluation of the constraints of current evidence from epidemiological studies." Nutrients 13, no. 10 (2021): 3601).”
Consequently, there does not exist a clear consensus in the scientific community on what cancers are encompassed by Applicant’s definition.
(Please note: for the purposes of examination, the Examiner is interpreting the cancers claimed to refer to the specific cancers recited in claims 3-4, 10-11)
Claims 5-11, 13, 16-20 depend on claim 1 and are likewise rejected for failing to remedy the ambiguity.
Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Tsukamoto et al (Tsukamoto, Hironobu, Tsutomu Mizoshita, Takahito Katano, Noriyuki Hayashi, Keiji Ozeki, Masahide Ebi, Takaya Shimura et al. "Preventive effect of rebamipide on N-methyl-N′-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats." Experimental and Toxicologic Pathology 67, no. 3 (2015): 271-277) discloses the prophylactic effect of rebamipide on MNNG-induced carcinogenesis similar to the working examples by Applicant. Chen et al (USPN 10,105,357 B2) teaches a method for treating cancer using antibiotics and rebamipide.
Response to Arguments
The Remarks of May 14, 2025 have been fully considered but are not fully persuasive for the reasons below.
35 USC 112(a)
Applicant’s Arguments:
“The Examiner has objected claims 1-20 under 35 U.S.C. 112(a), arguing that the specification, while being enabling for treating and preventing some types of cancer (i.e.: gastric and colorectal) and some patient populations (i.e.: mice), does not reasonably provide enablement for all types of cancer claimed and all types of patient populations claimed. However, the Applicant does not share this opinion and would like to present the following arguments. Based on the information provided in the present invention, one skilled in the art can practice the invention without being burdened with undue experimentation. The application discloses that rebamipide is able to prevent cancer development in a mouse model showing influence of increased intestinal permeability on colonic inflammation and cancer development in the intestine as well as in other parts of the body. Mice pre-treated with rebamipide recovered faster from the DSS treatment and also showed substantially lower incidence and size of tumors at the end of the study. In comparison to group C, mice in groups A and B had lower incidence (77% and 65%) and size (55% and 31%) of tumors as well as less tumors in non-intestinal tissues, such as breast, lung or liver. Histological examination revealed that in comparison to the untreated group, both rebamipide treated groups had higher proportion of adenomas than adenocarcinomas. It can be concluded that rebamipide treated groups were better protected from cancer development.”
Examiner’s Response:
The Examiner respectfully disagrees and reminds Applicant that as per MPEP 2164.08, “With respect to the breadth of a claim, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought by the claims. The Federal Circuit, citing McRO, provided guidance on the application of enablement to genus claims, holding that "[a]lthough a specification does not need to describe how to make and use every possible variant of the claimed invention, when a range is claimed, there must be reasonable enablement of the scope of the range." Sanofi-Aventisub, 987 F.3d at 1085 (internal quotations omitted). AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003);In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). See also Plant Genetic Sys., N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003) (alleged "pioneer status" of invention irrelevant to enablement determination).”
As aforementioned, although Applicant is enabled for treating and preventing some types of cancer (i.e.: gastric and colorectal) and some patient populations (i.e.: mice), does not reasonably provide enablement for preventing all types of cancer claimed and all types of patient populations claimed.
Applicant has failed to provide sufficient evidence demonstrating full enablement; however, the Examiner has provided evidence supporting that the results are known in the art to be unpredictable and issues with translating animal models to human patients, in addition to the additional evidence and arguments presented in accordance with Wands factor analysis as per MPEP 2164.01 (a) regarding undue experimentation factors. Applicant has additionally failed to provide an adequate response addressing these factors as outlined in detail by the Examiner.
The Applicant may not share this opinion; however, enablement is not determined by opinions, but is based on facts, evidence and persuasive arguments.
As per MPEP 2164.05, “Once the examiner has weighed all the evidence and established a reasonable basis to question the enablement provided for the claimed invention, the burden falls on applicant to present persuasive arguments, supported by suitable proofs where necessary, that one skilled in the art would be able to make and use the claimed invention using the application as a guide. In re Brandstadter, 484 F.2d 1395, 1406-07, 179 USPQ 286, 294 (CCPA 1973). The evidence provided by applicant need not be absolute but merely convincing to one skilled in the art, based on a preponderance of the evidence standard.”
Applicant’s Arguments:
“The Examiner has objected that the cancer is a broad class of heterogenous diseases for which there exists no general treatment or prophylaxis as there are more than 100 distinct types of cancer, and subtypes of tumors can be found within specific organs. However, the present invention is not related to prevention of any cancer, but only to those caused by carcinogens entering the body from the intestinal system due to the increased intestinal permeability. These carcinogens are unable to cross the gut wall or cross it at a relatively low rate under normal physiological conditions, but their passage into the body proper is substantially increased if a subject suffers from the increased intestinal permeability. The claims have been amended to include a feature “wherein said cancer is associated with increased translocation of carcinogens due to compromised intestinal barrier function and wherein said administration reduces intestinal permeability.”
Examiner’s Response:
The Examiner respectfully disagrees. Applicant’s definition is unclear of the cancers claimed by this definition based on what is known in the art as discussed above. Additionally, the cancers recited in claims 3-4 encompass a broad and heterogenous range of cancers varying the pathology, etiology, disease progression, treatment, etc. For example, Applicant’s definition is inclusive of both intestinal and non-intestinal malignancies such as pancreatic cancer, and also breast, skin, ovarian, and hemopoietic cancers. It is well-known in the art that these cancers are highly heterogenous and diverse. Applicant has provided no evidence supporting that instant invention is capable of preventing or even treating these broad range of cancers as claimed.
Applicant’s Arguments:
“The Examiner has further objected that even though administering a specific chemical compound to mice causes colon tumors and rebamipide administration reduced tumor size, this does not mean that the claimed invention is enabled for preventing and treating cancer in a person. The Applicant respectfully disagrees. It is a well-established practice among patent offices that the evidence required for filing a patent application is lower than for obtaining a marketing authorisation enabling to put the medicinal product on the market. In fact, due to the legal obligations to publish the upcoming clinical trials as well as their outcomes, it is impossible to include the results of human clinical trials in a patent application due to the novelty and nonobviousness requirements. In the present case, the application contains animal data showing on an established animal model usefulness of rebamipide in colorectal cancer treatment. The Applicant is not aware of any substantiated reason, why these data should not be transferable to humans.”
Examiner’s Response:
As aforementioned, the Examiner has applied the standard used in the test of enablement as per MPEP 2164.01. The Examiner has provided detailed Wands factor analysis discussing evidence and arguments as to why Applicant’s invention is not enabled for the full scope of patent protection sought.
As per MPEP 2164.02: “The issue of "correlation" is related to the issue of the presence or absence of working examples. "Correlation" as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a "working example" if that example "correlates" with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute "working examples."
Additionally, “For a claimed genus, representative examples together with a statement applicable to the genus as a whole will ordinarily be sufficient if one skilled in the art (in view of level of skill, state of the art and the information in the specification) would expect the claimed genus could be used in that manner without undue experimentation. Proof of enablement will be required for other members of the claimed genus only where adequate reasons are advanced by the examiner to establish that a person skilled in the art could not use the genus as a whole without undue experimentation.”
Again, Applicant as stated above has only provided data pertaining mice, specifically in vivo studies using a DSS model in mice to induce increased intestinal permeability and administration of PhIP (a compound found in red meat that is an alleged carcinogen) centered around studying colon cancer.
Applicant has provided no experimental data for the in vivo studies claimed to have been performed. Page 11 of Applicant’s specification lists various parameters claimed to have been observed; however, there is no actual data provided.
Although Applicant demonstrates that administering a specific chemical compound to mice causes colon tumors and rebamipide administration reduced tumor size, this does not mean that the claimed invention is enabled for preventing and treating cancer in a person.
Applicant has provided no support for any additional cancers recited in claims 4-5 and 11-12. Applicant has provided no support for the various risk factors recited in claims 5-6 and 8-10.
Applicant has provided no support for the elements of claim 7 involving combination therapies. Applicant has presented no studies exploring patient populations, patient populations at risk, and patients at various stages of cancer.
There is no mention of details identifying a population of subjects at risk or in need thereof, which would appear to include all populations. There is also no mention of populations that are at higher risk than others or any guidance for one in the art to identify who is at risk.
Applicant has performed no studies encompassing the wide range of cancer types listed within the claims, no studies encompassing the broad scope pertaining to subject, and no population studies for populations at risk for the conditions listed.
Consequently, as aforementioned, the issue is pertaining enablement with respect to the full scope of invention. Applicant has failed to provide support for prevention of cancer in the broad and heterogenous types of cancers claimed and to show that such results are translational in humans.
Applicant’s Arguments:
“The Examiner further questions the relationship between diet and cancer as still not well- established and inconsistent in the art. However, as explained in the present application it is not the diet in general, but rather carcinogens present in the diet that cause cancer and this teaching is well accepted among the healthcare professionals. Besides that the application itself provides evidence that PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), a carcinogen present in cooked meat, consistently caused tumors of various tissues in tested mice.”
Examiner’s Response:
The examiner respectfully disagrees and has presented evidence in the prior art disputing Applicant’s assertion that “this teaching is well accepted among healthcare professionals.” It is well-known in the art that the data is conflicting with regards to diet, cancer and carcinogens in food. Applicant has failed to provide additional evidence suggesting otherwise.
The Examiner further notes that no information disclosure statement has been filed by Applicant.
35 USC 102
Applicant’s Arguments:
“Claims 1 and 15-20 have been rejected under 35 U.S.C. 102(a)(1)(a)(2) as being anticipated by Cho et al (USPN 11,420,963 B2) (herein referred to as Cho). However, Cho is completely silent about increased intestinal permeability, and its relation to cancer development. In addition, the teaching of Cho is limited to a rebamipide prodrug. As explained in the section Claim interpretation, prodrugs of rebamipide are not intended to be in scope of the present invention. Therefore, the Applicant respectfully requests withdrawal of this rejection, in view of the limitation of the claims.”
Examiner’s Response:
First, the Examiner notes that claim interpretation used in applying prior art is based on the cancers recited in claims 3-4 due to the ambiguities aforementioned in defining the cancers claimed.
As aforementioned, prodrugs of rebamipide are included based on the specification and present scope of the claims. Cho additionally teaches in the Background Art properties associated with rebamipide itself (column 1, lines 26-67), including antiproliferative properties.
As aforementioned, Cho discloses” in addition to gastric ulcer, acute gastritis and chronic gastritis, rebamipide is known to have prophylactic and therapeutic effects on xerophthalmia, cancer, osteoarthritis, and rheumatoid arthritis.”
As per MPEP 2122, I-II: “"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
Furthermore, “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).”
Cho teaches gastroprotective properties for rebamipide and prophylactic and therapeutic effects on cancer. It is well-known in the art that rebamipide’s gastroprotective properties function to prevent colon cancer.
Applicant is further reminded that as per MPEP 2112.01, II: “"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”
Applicant’s Arguments:
“Tanigawa investigate the effects of rebamipide on gastric cancer cell growth. Their work demonstrates that rebamipide can inhibit gastric cancer cell proliferation in vitro, which may potentially be employed in the treatment of an already established gastric cancer by a direct anti- cancer mechanism. However, Tanigawa does not disclose or suggest prevention of cancer associated with increased intestinal permeability, nor a causal link between intestinal permeability, translocation of carcinogens, and cancer development. Therefore, the claimed invention is directed to a distinct therapeutic purpose, namely a method for preventing cancer, by a different mechanism of action, i.e., by restoring intestinal barrier integrity. In other words, it works indirectly by reducing increased intestinal permeability, thereby limiting translocation of carcinogens across the intestinal barrier.”
Examiner’s Response:
Similar arguments for Cho are applied for Tanigawa.
Particularly, as per MPEP 2122, I-II: “"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
Furthermore, “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).”
Applicant is further reminded that as per MPEP 2112.01, II: “"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”
Both Tanigawa and instant invention teach the same step of administering rebamipide to a subject with the identical condition; therefore, it is reasonable to conclude that the outcome will also be the same. As mentioned, discovering a new property does not make the claims patentable.
Applicant’s Arguments:
“Claim 1-3, 10-12, and 15 have been rejected under 35 U.S.C. 102(a)(1)(a)(2) as being anticipated by Murai et al. (Murai, R., T. Kanbe, T. Mukoyama, T. Shimomura, K. Hashiguchi, Y. Yoshida, H. Tsuchiya, Y. Hoshikawa, A. Kurimasa, and G. Shiota. "Effect of rectal administration of rebamipide on dextran sulfate sodium-induced colitis: role of hepatocyte growth factor." Inflammation Research 56 (2007): 240-245) (herein referred to as Murai). Specifically, the Examiner asserts that Murai teaches the prophylactic effects of rebamipide for colorectal cancer, including colon cancer. The cited passage (page 244, column 2, paragraph 3) states: "In IBD [inflammatory bowel disease], especially UC[ulcerative colitis], the repeated injury and repair may lead to an increase in the risk of colorectal cancer. Recently, HGF and c- Met was demonstrated to be highly expressed in the mucosa of UC and c-Met was increased in UC-associated colorectal cancer. These observations suggest that local expression of HGF may enhance the risk of colorectal cancer in the colonic mucosa of IBD via a cycle of repeated injury and repair. However, the blockade of this cycle by repair of colonic mucosa by rebamipide should reduce the genetic damage instead.”
The Applicant respectfully draws the Examiner’s attention to the fact that Murai teaches on multiple occasions that rebamipide upregulates HGF expression (e.g., abstract) that helps to
heal the intestinal mucosa by proliferation of epithelial cells. Unfortunately, this mechanism also enhances the risk of cancer via a cycle of repeated injury and repair (page 244, column 2, paragraph 3). At the same time, rebamipide treatment may help to break the cycle, and reduce the genetic damage. Thus, when the cited paragraph is read in the full context of the article, the message is more nuanced than the Examiner suggests. Rebamipide directly promotes cancer via HGF expression, but may also help to mitigate the damage caused by this expression. Therefore, Murai does not teach or suggest the use of rebamipide for the treatment or prevention of cancer. Rather, the study supports the conclusion that rectal administration of rebamipide is effective for treating DSS- induced colitis in mice (page 244, column 2, par. 4). Furthermore, Murai does not disclose or suggest prevention of cancer associated with increased intestinal permeability, nor a causal link between intestinal permeability, translocation of carcinogens, and cancer development. Accordingly, the cited reference does not anticipate the amended claims, and Applicant respectfully requests withdrawal of this rejection.”
Examiner’s Response:
Similar arguments for Cho and Tanigawa are applied for Murai.
Particularly, as per MPEP 2122, I-II: “"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
Furthermore, “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).”
Applicant is further reminded that as per MPEP 2112.01, II: “"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”
The Examiner respectfully disagrees with Applicant’s interpretation of Murai.
As mentioned by Murai, "In IBD [inflammatory bowel disease], especially UC[ulcerative colitis], the repeated injury and repair may lead to an increase in the risk of colorectal cancer. Recently, HGF and c- Met was demonstrated to be highly expressed in the mucosa of UC and c-Met was increased in UC-associated colorectal cancer. These observations suggest that local expression of HGF may enhance the risk of colorectal cancer in the colonic mucosa of IBD via a cycle of repeated injury and repair. However, the blockade of this cycle by repair of colonic mucosa by rebamipide should reduce the genetic damage instead.”
Instead, Murai teaches that rebamipide through promoting repair of the colonic mucosa, can disrupt the damaging cycle, and that by blocking this cycle, genetic mutations and damage leading to cancer development can be mitigated.
Consequently, Murai teaches chemoprevention of colorectal cancer using rebamipide. Applicant is invited to explain further how Murai teaches rebamipide promotes cancer as such a position is not consistent with Murai’s teachings, nor is it consistent with the state of the art where rebamipide is well-known as a gastroprotective agent and chemopreventative agent for gastric cancer.
Applicant’s Arguments:
“Claim 1-2, 4, 6-7, 9, 14, 16, and 18 have been rejected under 35 U.S.C. 102(a)(1)(a)(2) as being anticipated by Yasuda et al. (Yasuda, Takashi, Hiroshige Chiba, Takafumi Satomi, Akira Matsuo, Tadayoshi Kaneko, Daichi Chikazu, and Hironobu Miyamatsu. "Preventive effect of rebamipide gargle on chemoradiotherapy-induced oral mucositis in patients with oral cancer: a pilot study.” Journal of Oral & Maxillofacial Research 2, no. 4 (2012): e3.) (herein referred to as Yasuda). However, the Applicant respectfully submits that this objection is unfounded. Yasuda et al. disclose the use of rebamipide for the prevention of oral mucositis in patients with oral cancer undergoing chemoradiotherapy (specifically, daily radiotherapy combined with docetaxel). It is important to note that within the context of this study, the rebamipide gargle was not employed for the treatment of cancer itself, but solely for mitigating the adverse effects associated with chemoradiotherapy. Furthermore, Yasuda et al. do not mention increased intestinal permeability, nor do they discuss the role of carcinogens or the enhanced passage of such substances into systemic circulation in individuals exhibiting increased intestinal permeability. As such, the teachings of Yasuda et al. do not anticipate the claimed invention, which addresses a fundamentally different therapeutic approach and physiological target. In view of the foregoing, the Applicant considers the objection under anticipation to be moot and respectfully requests withdrawal of this rejection.”
Examiner’s Response:
The Examiner respectfully disagrees, and similar arguments for Cho and Tanigawa are applied for Yasuda.
Particularly, as per MPEP 2122, I-II: “"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
Furthermore, “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).”
Applicant is further reminded that as per MPEP 2112.01, II: “"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”
Furthermore, Applicant has broadly defined treatment on page 6, lines 23-27 as “a therapy that is able to slow, stop, inhibit or reverse the disease. It is also meant to cover reduction or alleviation of clinical symptoms of the disease.”
Therefore, using broadest reasonable interpretation, Yasuda’s teachings using rebamipide for the prevention of oral mucositis in patients with oral cancer is encompassed by the scope of the claims.
35 USC 103
Applicant’s Arguments:
Due to the amendments made, the Applicant believes that the claims cannot be considered obvious.
Examiner’s Response:
The examiner respectfully disagrees and maintains the 35 USC 103 rejection accordingly based on the arguments presented.
Prior Art
Applicant’s Arguments:
Due to the amendments made, the Applicant believes that the claims cannot be considered obvious.
Examiner’s Response:
The examiner respectfully disagrees and maintains Tsukamoto et al (Tsukamoto, Hironobu, Tsutomu Mizoshita, Takahito Katano, Noriyuki Hayashi, Keiji Ozeki, Masahide Ebi, Takaya Shimura et al. "Preventive effect of rebamipide on N-methyl-N′-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats." Experimental and Toxicologic Pathology 67, no. 3 (2015): 271-277) and Chen et al (USPN 10,105,357 B2) as relevant art to Applicant’s disclosure.
Again, Applicant themselves have not submitted an information disclosure statement.
Specificity of Cancer Type Addressed
Applicant’s Arguments:
The Examiner's concern regarding the broad and heterogeneous nature of cancer is addressed by clarifying that the claimed invention is limited to cancers caused by increased intestinal permeability. The claims have been amended accordingly to restrict their scope to cancers associated specifically with increased translocation of carcinogen due to compromised intestinal barrier function.
Examiner’s Response:
Applicant’s amendments do not clarify the scope of invention, but create further ambiguity as elaborated in the new rejections section.
As aforementioned, aside from Applicant’s definitions of cancers claimed, Applicant is not enabled for prevention for the wide range of heterogenous cancers claimed, simply based on the specific cancers claimed in claims 3-4 as discussed above.
Applicant’s Arguments:
Specificity of Cancer Type Addressed
The Examiner's concern regarding lack of human data is unfounded, as patent law generally does not require clinical trial results for enablement. The application includes data from an established animal model demonstrating the effect of rebamipide in reducing tumor burden. These results are sufficient to support the claimed invention, consistent with standard practice, and there is no substantiated reason to question their translatability to human application.
Examiner’s Response:
The Examiner has already addressed the points associated with the test of enablement commensurate with scope of invention, particularly with respect to the working example provided by Applicant. Again, the issue is not regarding providing clinical trials, but in providing sufficient support to enable the full scope of invention.
Applicant’s Arguments:
Mechanism of action: The invention is based on the prevention of cancer through restoration of intestinal barrier integrity, a mechanism not disclosed or suggested in either Tanigawa, Murai, Yasuda or any other cited reference. These pieces of prior art do not address increased intestinal permeability as a factor in carcinogenesis.
Examiner’s Response:
As previously discussed, as per MPEP 2122, I-II: “"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
Furthermore, “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).”
As discussed above, Tanigawa, Murai and Yasuda teach gastroprotective effects and antiproliferative properties of rebamipide. Additionally, such properties of rebamipide are well-established in the prior art. Discovering a new mechanism does not make the claims patentable. Applicant has failed to provide any support as to how their invention provides any additional process steps to differentiate from the prior art disclosures regarding therapeutic use of rebamipide, which is a known drug with known gastroprotective and antiproliferative properties.
Applicant’s Arguments:
Importance of the invention: Cancer represents a severe condition greatly reducing quality of life. As it is among the primary mortality reasons, the patients need to get checked more often, thereby increasing pressure on healthcare system. Refusing the present invention would jeopardize any subsequent research that wouldn't make sense without patent protection. Especially since the many types of cancer do not have any effective treatment, we think that any progress in such field needs to be encouraged.
Examiner’s Response:
Applicant is reminded that “Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).”
Rebuttal evidence may include evidence of "secondary considerations," such as "commercial success, long felt but unsolved needs, [and] failure of others." Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 4459, 467. See also, e.g., In re Piasecki, 745 F.2d 1468, 1473, 223 USPQ 785, 788 (Fed. Cir. 1984); however, Applicant is further reminded that “in other words, in order for evidence of secondary considerations to be accorded substantial weight, there must be a nexus, i.e., a legally and factually sufficient connection or correspondence between the submitted evidence and the claimed invention. Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366, 1373, 2019 USPQ2d 483355 (Fed. Cir. 2019), cert. denied, 141 S.Ct. 373 (2020).
The Examiner acknowledges the importance of cancer prevention; however, these statements alone are insufficient in overcoming the rejections set forth pertaining indefiniteness, enablement, anticipation, and obviousness.
Applicant’s Arguments:
Limitation to prevention: The present invention is directed to a method for preventing cancer, rather than treating existing cancers. In contrast to the cited prior art, which at most may be interpreted as disclosing or suggesting methods for the direct treatment of specific types of cancer, the present invention provides an indirect prophylactic approach. Specifically, cancer prevention is achieved by reducing increased intestinal permeability, thereby limiting the translocation of carcinogens into the body. This mechanism and therapeutic strategy are neither disclosed nor suggested in the prior art.
Examiner’s Response:
As discussed, the gastroprotective properties and chemoprevention of gastric cancer is well-known in the art for rebamipide. As previously stated, the instant invention is not enablement for the full scope of invention.
Consequently, for the reasons stated, Applicant’s arguments are not persuasive.
Conclusion
Claims 1-13 and 16-20 are under consideration and remain rejected.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN L. LADD whose telephone number is (703)756-5313. The examiner can normally be reached M-Th, 7:00 am to 5:30 pm EST.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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