CTNF 18/699,471 CTNF 90102 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Priority The instant application is the national stage entry of PCT/JP2022/037897 filed 11 October 2022. Acknowledgement is made of the Applicant’s claim of foreign priority to application JP2021-168413 filed 13 October 2021. Claim Rejections - 35 USC § 112 07-30-01 AIA 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. 07-31-03 AIA Claim s 31-36 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 treating dermatitis , does not reasonably provide enablement for treatment or prevention of all inflammatory diseases . 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. The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands , 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: 1) scope or breadth of the claims; 2) nature of the invention; 3) relative level of skill possessed by one of ordinary skill in the art; 4) state of, or the amount of knowledge in, the prior art; 5) level or degree of predictability, or a lack thereof, in the art; 6) amount of guidance or direction provided by the inventor; 7) presence or absence of working examples; and 8) quantity of experimentation required to make and use the claimed invention based upon the content of the supporting disclosure. When the above factors are weighed, it is the Examiner’s position that one skilled in the art could not predictably practice the full breadth of the invention without undue experimentation. Scope or breadth of the claims The claims are broader in scope than the enabling disclosure. The specification merely discloses, without more, some examples of inflammation-related diseases such as dermatitis (see Examples). The Applicant has shown that the claimed compound is effective at reducing edema by pre-treating infected mice, as measured by a dermatitis score [0065]. The Applicant indicates suppression of IL-4, IL-1 b , IL-6, TSLP, and IL-33 and says these cytokines are linked to various skin diseases [0065]. The specification does not provide factual evidence showing the enablement of the claimed method on additional skin inflammatory diseases, such as eczema or psoriasis nor does it provide enablement for total prevention thereof. Nature of the invention The nature of the invention is directed to a method of treating or preventing inflammatory comprising administering a composition comprising a -linolenic acid and diacylglycerol to a subject. Dependent claims 32-36 specify the inflammatory disease in a list of species and narrow the concentration ranges. Relative level of skill possessed by one of ordinary skill in the art The relative level of skill possessed by one of ordinary skill in the art of medical research is relatively high, as a majority of lead investigators directing scientific research and development in this particular technological area possess an Ph.D. in a scientific discipline such as organic synthetic chemistry, polymer chemistry, medicinal chemistry, biochemistry, pharmacology, biology or the like. State of, or the amount of knowledge in, the prior art It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity relating to the treatment of inflammatory disease is generally considered to be an unpredictable factor. Unpredictability in treating inflammation generally is established by the following references: Ahmed (Front. Biol. 2011, 6(4): 274–281) teaches that inflammation is a response by the immune system during infection and injury (abstract). The molecular mechanism of inflammation is taught as being very complicated and various examples of pathways are provided (abstract). At the molecular level, many pathways are involved in the inflammatory response including pattern-recognition receptors (PRRs), which include TLRs, CLRs, RLRs, and NLRs (pg 275, ¶2). NF- is identified as being a transcription factor that is activated by the aforementioned PRRs (pg 275, ¶4). In addition, inflammatory response can be coordinated by proinflammatory cytokines such as TNF, IL-1 , and IL-6 (pg 275, ¶3). In the case of viral infection, inflammation is induced by type-1 IFNs which induce phosphorylation of ISGF3 (pg 275, ¶3). ISGF3 then activates PKR and OAS (pg 275, ¶3). In addition to NF- , other transcription factors that contribute to the inflammatory response include AP-1, CREB, E2F, and SRF (pg 276, ¶1). Furthermore, an array of epigenetic mechanisms are also known for regulation of inflammation including the acetylation of histone H3 on inflammatory genes initiates a response (pg 276, ¶4). DNA methylation is also essential for many inflammatory gene regulation and inflammatory response is known to be associated with DNA hypomethylation at the promoter of TLR2 gene (pg 277, ¶1). Moreover, microRNAs are known to regulate the expression of target genes through interaction with mRNAs and have been reported as being important regulators of inflammatory response (pg 277, ¶1). Ahmed concludes that most chronic inflammatory conditions lack a defined and continuing inducer, making therapeutic intervention for those diseases quite unfeasible (pg 279, ¶2). Atopic dermatitis, one disease that is characterized by inflammation, has no known single cause and is instead believed to be caused by a variety of mechanisms. Among those are included gene mutations, skin cell defects, and bacteria or viruses on the skin (DermNetNZ, page 1, ¶1-3). Thus, a compound that can treat the bacterial causes of atopic dermatitis may not be able to simultaneously treat the viral causes. Thaiwat teaches that atopic dermatitis can often be recalcitrant to medications such as lubricants, antihistamines, and corticosteroids (summary). Omalizumab, which is an anti-IgE antibody, is shown as being useful for treating atopic dermatitis (summary; pg 357, ¶3). Zumla teaches, in a 2013 review of tuberculosis, the current state of tuberculosis treatments, which include isoniazid, rifampin, ethambutol, pyrazinamide, fluoroquinolones, ethionamide, prothionamide, cycloserine, and para-aminosalicylic acid (Tables 1 and 2). The aforementioned agents are all antibiotics or chelating agents and it is noted that none of them are anti-IgE antibodies such as omalizumab. Absent specific evidence to the contrary, the state of the art, as taught above by Ahmed, suggests the method of the instant claims would not predictably be effective in treating any form of inflammation as multiple pathways, some related and some unrelated, contribute to the inflammatory response. Moreover, Ahmed discloses that because of the lack of a defined inducer, therapeutic intervention for chronic inflammation is very difficult. Level or degree of predictability, or a lack thereof, in the art The art teaches that many different pathways and molecular targets contribute to the mechanism of inflammation. Moreover, it is shown that a drug suitable for atopic dermatitis, omalizumab, is not suitable or known for use with other diseases associated with inflammation (according to the instant claims) such as tuberculosis. In fact, IgE antibodies are not even discussed as being therapeutic targets of tuberculosis. As such, an agent that is suitable for treating one inflammatory disease would not necessarily or predictably be useful for every disease associated with inflammation. Moreover, the art teaches that many unrelated pathways contribute to general inflammation rendering treating inflammation as a whole as nearly impossible. Amount of guidance or direction provided by the inventor The Applicant was required to provide in the specification additional guidance and direction with respect to the use of the claimed subject matter in order for the application to be enabled with respect to the full scope of the claimed invention. However, the Applicant has not provided guidance on how to use their claimed invention with all inflammatory skin diseases. Although the instant specification discloses treating dermatitis in rats it remains silent on the utility of the claimed invention in treating every type of inflammatory skin disease that exists. Presence or absence of working examples The specification fails to provide scientific data and working embodiments with respect to all inflammatory and immune diseases that will work in this invention. Example 1 provides support for the in vivo treatment of dermatitis with the instant invention and the suppression of cytokines IL-4, IL-1 b , IL-6, TSLP, and IL-33 (pgs 35-44). However, these examples do not enable treating all inflammatory skin diseases. Quantity of experimentation required to make and use the claimed invention based upon the content of the supporting disclosure One of ordinary skill in the art would have to conduct a myriad number of experiments comprising picking and choosing patients or subjects with various known inflammatory skin diseases, administering the claimed invention, and testing for efficacy. The art teaches that inflammation is a complicated response with many known causes and mechanisms. Ahmed teaches that most chronic inflammatory conditions lack a defined and continuing inducer, making therapeutic intervention for those diseases quite unfeasible. DermNetNZ teaches that atopic dermatitis is caused by various stimuli such as bacterial or viral infections, gene mutations, or skin cell defects. Thaiwat teaches that omalizumab, which is an anti-IgE antibody, is effective at treating atopic dermatitis. Zumla teaches tuberculosis, an additional disease associated with inflammation, which is treated with a variety of antibiotics and chelating compounds. Zumla does not teach using omalizumab or an anti-IgE antibodies as useful for treating tuberculosis. Thus, omalizumab, which is useful for treating atopic dermatitis, an inflammatory disease, is not useful for treat tuberculosis and accordingly cannot be presumed to be suitable for all inflammatory diseases. That being said, the state of the art verifies that a treatment for one inflammatory disease would not necessarily be suitable for all inflammatory diseases. As the Applicant has provided only evidence of efficacy for dermatitis in a rat model, it would be unpredictable to extrapolate that data for treating all known inflammatory skin diseases. Moreover, the Applicant has provided no evidence of enabling full prevention of skin inflammation in all disease conditions. For a compound or genus to be effective against inflammation generally is thus contrary to the present understanding of medical science. Thus, it is not reasonable for any agent to be able to treat inflammation generally. That is, the skill is so low that no compound effective generally against inflammatory disorders has ever been found. In terms of the individual inflammatory disorders, this is completely varied. One of ordinary skill in the art knows that, treatments for inflammation must often be tailored to the particular type of inflammation present, as there is no, and there can be no, "magic bullet" against inflammatory disorders generally. Because of the sheer scope of this claim language, dozens of unrelated diseases will have to be tested. Due to the complex mechanisms and varied causes of skin inflammation, complete prevention thereof is considered to be impossible. MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright , 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here. Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success. Therefore, in view of the Wands factors discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation, with no assurance of success, to test which inflammatory skin disease, among thousands, would produce desired activity with the claimed invention . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 31-36 are rejected under 35 U.S.C. 103 as being unpatentable over Couzy et al. (US 7,479,286) in view of Ishikawa et al. (US 2006/0029643). Couzy teaches a food composition intended for improving skin health and for preventing or regulating the growth of skin pathogens and microflora, wherein the composition comprises anti-microbial fatty acids (abstract). The fatty acid may be a -linolenic acid and may be in amounts of at least 5%, or amounts sufficient to improve or maintain skin health (col 2, lns 21-30; col 3, lns 5-7). Couzy teaches that a -linolenic is known to inhibit inflammatory reactions on the skin (col 1, lns 48-51). Couzy also teaches it as being active against Malassezia pachydermatis , which is a yeast known to cause seborrheic dermatitis (col 2, lns 15-20). The concentration of a -linolenic acid can be increased by dietary means (col 10, lns 37-40). The purpose the dietary lipids, in addition to improving skin health, is to maintain an adequate barrier function of the skin (col 3, lns 26-29). There can be situations where the barrier function of the skin becomes insufficient due to changes in physiological, environmental, or pathological conditions and the skin can adapt by increasing skin lipids (col 1, lns 35-40) . Couzy does not teach wherein the composition further comprises diacylglycerol nor does it teach the claimed concentrations. Ishikawa teaches a food containing a glycosylated ceramide and a diacylglycerol [0010]. The diacylglycerol, when incorporated in a food with the ceramide, increases the amount of ceramide in the stratum corneum and thus remarkably improves the barrier function of the skin [0024]. The diacylglycerol can be incorporated in concentration from 0.01-20% [0026]. It would have been prima facie obvious to prepare the oral composition of Couzy comprising a -linolenic acid for the improvement of skin health wherein the a -linolenic acid is present in amounts of at least 5%. Moreover, it would have been obvious to combine the oral food product of Ishikawa, which comprises diacylglycerol and glycosylated ceramide, into the oral product of Couzy. Since Couzy teaches that there can be situations where the barrier function of the skin becomes insufficient due to changes in physiological, environmental, or pathological conditions and that increasing skin lipids help correct this situation, it would have been obvious to modify the oral dosage to include a barrier function improving agent like diacylglycerol. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use (see MPEP § 2144.07). Regarding the amount of diacylglycerol, Ishikawa teaches a range of from 0.01-20%, however due to the ability of diacylglycerol to improve the skin barrier function, it would have been obvious to optimize the amounts thereof. That being said and in lieu of objective evidence of unexpected results, the concentration of diacylglycerol can be viewed as a variable which achieves the recognized result of successfully improving the skin barrier function. The optimum or workable range of diacylglycerol concentration can be accordingly characterized as routine optimization and experimentation (see MPEP 2144.05 (II)B). “[Discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276 (CCPA 1980). Appellants provide no evidence of any secondary consideration such as unexpected results that would render the optimized amounts of diacylglycerol concentration nonobvious. The skilled artisan would have found it obvious to take the composition of Couzy and Ishikawa and use it in a method of treating skin inflammation, such as seborrheic dermatitis as caused by M. pachydermatis , in a subject in need thereof, as well as a method of improving the skin barrier function based on the known properties of diacylglycerol. Claims 31-36 are accordingly rejected as obvious in view of the prior art. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW S ROSENTHAL whose telephone number is (571)272-6276. The examiner can normally be reached M-F 8-5pm EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /ANDREW S ROSENTHAL/ Primary Examiner, Art Unit 1613 Application/Control Number: 18/699,471 Page 2 Art Unit: 1613 Application/Control Number: 18/699,471 Page 3 Art Unit: 1613 Application/Control Number: 18/699,471 Page 4 Art Unit: 1613 Application/Control Number: 18/699,471 Page 5 Art Unit: 1613 Application/Control Number: 18/699,471 Page 6 Art Unit: 1613 Application/Control Number: 18/699,471 Page 7 Art Unit: 1613 Application/Control Number: 18/699,471 Page 8 Art Unit: 1613 Application/Control Number: 18/699,471 Page 9 Art Unit: 1613 Application/Control Number: 18/699,471 Page 10 Art Unit: 1613 Application/Control Number: 18/699,471 Page 11 Art Unit: 1613 Application/Control Number: 18/699,471 Page 12 Art Unit: 1613 Application/Control Number: 18/699,471 Page 13 Art Unit: 1613
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