DETAILED ACTION
This office action is in response to applicant’s filing dated March 8, 2023.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 9-16 are pending in the instant application. Acknowledgement is made of Applicant's amendments filed March 8, 2023. Acknowledgement is made of Applicant's cancelation of claims 1-8; and addition of new claims 9-16.
Claims 9-16 are presently under examination.
Priority
The present application is a 371 of PCT/KR2021/012578 filed on September 18, 2021, which claims benefit of foreign priority to REPUBLIC OF KOREA 10-2020-0120568 filed on September 18, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on March 8, 2023 and April 29, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
Acknowledgement is made of the drawings received on March 8, 2023. These drawings are accepted.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
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 9-16 are 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 a method for treating graft versus host disease (GVHD) comprising administering a pharmaceutical composition comprising fursultiamine or benfotiamine, does not reasonably provide enablement for a method of preventing graft versus host disease. 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.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention relates to a method for preventing or treating graft versus host disease (GVHD) comprising administering a pharmaceutical comprising administering a pharmaceutical composition comprising a thiamine derivative of chemical formula (1). Claims 10 further narrow the limitations of the thiamine derivative to encompass the specifically claimed R group. Claim 11 further narrows the limitations of the thiamine derivative to fursultamine, allithiamine, and benfotiamine. Claims 13-16 relate to a method for alleviating graft versus host disease (GVHD) comprising administering a pharmaceutical comprising administering a pharmaceutical composition comprising a thiamine derivative of chemical formula (1). Claims 14 further narrow the limitations of the thiamine derivative to encompass the specifically claimed R group. Claim 15 further narrows the limitations of the thiamine derivative to fursultamine, allithiamine, and benfotiamine.
The relative skill of those in the art is high, generally that of a D.V.M. or Ph.D. The artisan using Applicant’s invention would generally be a veterinarian with a V.M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art, the examiner cites Saidu et al (Frontiers in Immunology, 2020; 11:578314 pp 1-19).
Saidu teaches GvHD (graft-versus-host disease) is a complication that often occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in up to 50% of cases, where donor T- and B cells derived from the graft recognize and attack host antigens (page 2, left, 1st paragraph); the authors defined cGvHD-specific organ manifestations and elaborated a scoring system by considering the severity of involvement of skin, mouth, eyes, gastrointestinal tract, liver, lungs, joint fascia, and genital tract differently from other hematological diseases, and from models for testing conditioning or immunosuppressive regimens; unfortunately, the existing murine models of cGvHD fail to fully include the whole spectrum of human cGvHD symptoms, which makes it difficult to treat and to draw general conclusions about the efficacy of new therapeutic approaches based on animal models (page 2, right, 1st paragraph); the psychological and economic impact of cGvHD is still enormous, as many complications can emerge from both the disease and its treatment; chronic GvHD impairs the quality of life of the affected patients who require a continued medical follow-up, with higher risk of infection and death; even the administration of corticosteroids is problematic: in a cohort of 162 patients, it was clearly demonstrated, that cGvHD and steroid treatment significantly prolonged time to recover normal body mass index (BMI) and muscle strength after HSCT (page 3, right, 3rd paragraph). Saidu teaches standard of care in the treatment of cGvHD depends on the particular organ(s) or site(s) that is/are affected and adopted treatments can be topical or systemic; nevertheless, about 50%-60% of patients with cGvHD will require a second-line treatment within 2 years, but at the moment there is no consensus on the optimal choice of agents for second or further lines of therapy; the National Comprehensive Cancer Network (NCCN) guidelines and the European Society for Blood and Marrow Transplantation (EBMT) consensus, both edited in 2020, agree in the use of steroids as first-line treatment, and sustain the use of ibrutinib, the only compound approved by the FDA for second- or further line treatment of cGvHD; nevertheless, both guidelines clearly state that there are still no standard therapies for steroid-resistant (SR) patients, limiting the patients to the listed available drugs, and advising clinicians to possibly enroll these patients into clinical trials (page 4, right, last bridge paragraph). Saidu teaches new strategies seem to offer great opportunities for preventing or reversing cGvHD, as they are aimed at repairing/maintaining immune regulation by targeting B cell (responsible for the production of self-reactive antibody complexes) or T cell (responsible for pro-inflammatory and pro-fibrotic cytokine production) signaling and by reducing inflammation, which is fundamental in the pathogenesis of cGvHD; however, the biggest drawback for some of these emerging therapies for cGvHD is the available evidence for their tolerability and efficacies, which is frequently from preclinical or clinical trials that are trivial and often conflicting (page 13, right, 3rd paragraph). Saidu teaches profound knowledge gaps in fully understanding the biology of cGvHD have until now mired the discovery and implementation of effective therapeutic strategies (page 14, left, last paragraph).
Thus, Saidu establishes that the art of developing therapeutics and treating and preventing graft versus host disease is extremely unpredictable.
2. The breadth of the claims
Claims 9-16 are narrow in terms of the compounds claimed to be useful for treating and preventing graft versus host disease. The instant claims do not require that an individual is in need of preventing, treating or alleviating graft versus host disease or that the compound to be administered by administered in an effective amount. Thus, the claims encompass the administration of the claimed compounds to any subject in any amounts.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides examples wherein the effect of benfotiamine, allithiamine, and fursultiamine on allo-reactive CD4+IFNg+ T cell generation in in vitro cells is investigated and disclose that benfotiamine showed no significant difference in degree of CD4+IFNg+ T cell generation, while allithiamine and fursultamine showed a significant reduction compared to positive control (See Example 2). The specification further provides an example of fursultiamine in a mouse model of GVHD wherein CD4+IFNg+ T cell generation is reduced. However, the specification does not provide any data that shows that any of the claimed compounds prevent graft versus host disease in any subject.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that any of the claimed thiamine derivatives could be predictably used to prevent graft versus host disease.
Determining if a particular thiamine derivative compound will prevent graft versus host disease would require formulation into a dosage form, and subjecting into clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the inventions of claims 9-16 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Claim Rejections - 35 USC § 112(d)
Failing to Further Limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 11 and 15 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 is directed to a method for preventing or treating graft versus host disease (GVHD), comprising step of: administering a pharmaceutical composition comprising at least one compound selected from the group consisting of a thiamine derivative represented by chemical formula 1 below and a pharmaceutically acceptable salt thereof to a subject [Formula 1].
Claim 13 is directed to a method for alleviating graft versus host disease (GVHD), comprising step of: administering a food composition comprising at least one compound selected from the group consisting of a thiamine derivative represented by chemical formula 1 below and a pharmaceutically acceptable salt thereof to a subject [Formula 1].
Claim 11, which depends from claim 9, and claim 15, which depends from claim 13, recite: wherein the thiamine derivative is at least one selected from the group consisting of fursultiamine, allithiamine, and benfotiamine.
Benfotiamine has the structure:
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509
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Benfotiamine does not contain the disulfide and hydroxy moieties required by Formula (1) or either of the R moieties. Thus, benfotiamine is outside the scope of formula (1). Thus, the limitations of claims 11 and 15 are broader than those of the claims from which they depend and do not further limit the scope of the claims from which they depend. Claims 11 and 15 are of improper dependent form for failing to further limit the subject matter of the claim upon which they depend.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 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 9, 11, 13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (WO 2016/015634 A1).
Examiner’s Note: Claim 11 and claim 15, which depend from and thus incorporate all the limitations of claims 9 and 13, encompass wherein the thiamine derivative is benfotiamine which is not encompassed by the thiamine derivative formula of claims 9 and 13. Claims 9 and 13 are rejected in as far as benfotiamine reads on the thiamine derivative.
Liu teaches a method for treating a liver disease comprising administering to a subject in need thereof a composition comprising (a) berberine or a derivative or analog thereof; and (b) one or more pharmacologically active organic acids, in a therapeutically effective amount, and (c) optionally a pharmaceutically acceptable excipient, carrier, or diluent (claim 17); wherein the pharmaceutical composition further comprises benfotiamine (claim 27). Liu teaches liver disease includes graft-versus-host disease of the liver [0019].
While the reference may not be anticipatory insofar as one must select benfotiamine from various agents and graft-versus-host-disease from various liver diseases as taught in Liu, it remains that it would have been obvious to a person of ordinary skill in the art, to have selected this particular compound detailed supra from the list of additional agents and graft-versus-host-disease in order to arrive at a method of treating GVHD comprising administering benfotiamine. The skilled person would have been motivated to do so by the unambiguous disclosure of each particular species of active agents individually and alternatively as equally useful in a method of treating liver diseases including GVHD. This conclusion is supported by the fact that it has long been held in patent prosecution that a reference should be considered as expansively as is reasonably possible in determining the full scope of the contents within its four corners.
Taken together, all this would result in the practice of the method of claims 9, 11, 13, and 15 with a reasonable expectation of success.
Conclusion
Claims 9-16 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628