DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
2. Applicant has not filed an English language translation of foreign priority Korean Application No. KR10-2021-0021526. It is suggested that a certified translation of every foreign benefit application or Patent Cooperation Treaty (PCT) application not filed in English be submitted. See 35 U.S.C. 119(b)(3) and 372(b)(3) and 37 CFR 1.55(g)(3)(i) and 41.154(b). A showing of priority that relies on a non-English language application is prima facie insufficient to overcome an intervening reference if no certified translation of the application is on file. See 37 CFR 41.154(b) and 41.202(e).
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on August 17, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner, please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith.
Specification
4. The disclosure is objected to for the following reasons:
The Specification recites, “Example 1: Preparation method of novel sesquiterpene derivative”, (page 22, line 18). It is suggested that the term “novel” be deleted from this recitation. Once the determination of the novelty of a claimed invention has been established and the disclosure of the invention made public and/or patented, the claimed invention is no longer novel, since the scope of the invention no longer embraces what is considered “novel.” Thus, the incorporation of “novel” into the language of the Specification is not appropriate. Appropriate correction is required. See MPEP § 608.01.
Claim Rejections - 35 USC § 112
5. 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.
6. Claims 8 and 9 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.
7. Claim 8 is drawn to the pharmaceutical composition comprising the sesquiterpene derivative of claim 4, further comprising:
“the sesquiterpene derivative or a pharmaceutically acceptable salt thereof; and one or more additional ingredients selected from…”.
This recitation is confusing because it is unclear if Applicant is intending to recite an additional sesquiterpene derivative (i.e., in addition to the sesquiterpene derivative required by claim 4) OR if the sesquiterpene derivative recited in line 3 refers to the sesquiterpene derivative previously recited in the composition of claim 4.
8. Claim 9 is drawn to the pharmaceutical composition of claim 8, and recites in line two:
“wherein the pharmaceutical composition has formulations of powders, granules, tablets, capsules or injections.”
However it is not clear what is meant by the recitation that “the pharmaceutical composition has formulations of powders, granules…,” i.e., does Applicant intend for the powders, granules, tablets, capsules or injections to refer to additional components contained in said recited pharmaceutical composition, OR does the pharmaceutical composition exist as a formulation in the form of a powder, a granule, a tablet, a capsule, or an injectable formulation.
Clarification is requested.
9. 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.
10. Claims 1-13 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. In particular, support cannot be found for the full scope of sesquiterpene derivatives represented by Chemical Formula 1, as instantly claimed.
11. The MPEP §2163 states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. In the case of chemical entities, Applicant's attention is further directed to Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), which notes that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, “not a mere wish or plan for obtaining the claimed chemical invention.” While the court recognizes that, “[i]n claims involving chemical materials, generic formulae usually indicate with specificity what the generic claims encompass” (Id.), it is also recognized that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim and/or the genus must be sufficiently detailed to show that applicant was in possession of the claimed invention as a whole (see Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991)). If a genus has substantial variance, the disclosure must present a sufficient number of representative species that encompass the genus in order to adequately describe the genus (i.e., the disclosure must describe a sufficient variety of species to reflect the variation within that genus). See MPEP § 2163. Otherwise, as stated by the court in Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company (Fed. Cir. 2010), “a generic claim may define the boundaries of a vast genus of chemical compounds, and yet the question may still remain whether the specification, including original claim language, demonstrates that the applicant has invented species sufficient to support a claim to a genus.
12. In the instant case, it is evident that the genus of sesquiterpene derivatives embraced by Chemical Formula 1 has substantial variance. For example, the “X” variable can be one of four moieties selected from phenyl, 2-oxo-dioxole, cyclohexyloxycarbonylpropanate, and phenylacrylate, each of which is additionally optionally substituted by alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl moieties, bearing no structural resemblance to one another what-so-ever. Indeed, the genus is virtually without limit, embracing hundreds of millions of potential compounds. Yet, the instant Specification discloses the preparation of only approximately 29 structurally related compound species within the genus of Chemical Formula 1 (see pages 24-51).
13. While the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad generic. For example, in In re Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d 1008 (Fed. Cir. 1989). In the instant case, it is similarly determined that the disclosure of 29 structurally related compounds does not adequately describe a subgenus embracing hundreds of millions of additional compound species bearing no structural relationship with those 29 disclosed compounds. That is, the Specification does not disclose a sufficient variety of species to reflect the extreme variance in the genus.
14. The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
15. As such, claims 1-13 are rejected.
16. Claims 4-13 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 the sarcopenia inhibiting effect of Compound 1-1 and Compound 1-2 in Experimental Examples 1-4 (Specification, pages 53-57), does not reasonably provide enablement for treating or preventing sarcopenia comprising administering any compound represented by Chemical Formula 1. 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.
17. The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below.
18. Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
19. In the instant case, the claimed invention pertains to a composition for preventing or treating sarcopenia comprising a sesquiterpene derivative represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof (claims 4-9), or a food/ feed/cosmetic composition for preventing or ameliorating sarcopenia (claims 11-13). Claim 10 is drawn to a method of treating or preventing sarcopenia comprising administering a sesquiterpene derivative represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof, to a subject. It is noted that the claim 10 fails to define a distinct patient population, i.e., a subject in need thereof.
20. The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he 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” and, as stated in MPEP 2164.05(b), “[t]he 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.”
21. As discussed above, the instantly claimed invention pertains to methods of administering a sesquiterpene derivative of Chemical Formula 1 to treat or prevent sarcopenia, or a composition comprising a sesquiterpene derivative of Chemical Formula I to alleviate or prevent sarcopenia, wherein said sesquiterpene derivatives are alleged by the Specification to inhibit the expression of myostatin mRNA in muscle cells, or to inhibit the expression of MURF1 mRNA, or inhibit the expression of Foxo3. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that – due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc) would interact with the given target to elicit a related biological response.
22. The level of skill to practice the art of the instantly claimed invention is high and requires a variety of skills usually found in institutions and companies that employ highly trained and skilled scientists to carry out these tasks.
23. In this case, the state of the art regarding sarcopenia treatment is that, “[s]arcopenia is characterized by loss of muscle and reduction in muscle strength that contributes to higher mortality rate and increased incidence of fall and hospitalization in the elderly. Mitochondria dysfunction and age-associated inflammation in muscle are two of the main attributors to sarcopenia progression. Recent clinical trials on sarcopenia therapies such as physical exercise, nutraceutical, and pharmaceutical interventions have revealed that exercise is the only effective strategy shown to alleviate sarcopenia,” (Lo et al., J Orthop Translat 2020, see abstract).
24. The state of the art regarding the sesquiterpene derivative Cedrol, a naturally occurring sesquiterpene alcohol, is that the (+)-cedrol isomer has biological efficacy that has been quantified across various studies, (i.e., cytotoxicity against cancer cell lines, immunomodulatory effects, and inhibitory activity against fungal pathogens), and targets multiple signaling pathways, such as PI3K/Akt/mTOR and NF-κB (see webpage printout of BenchChem.com, Tables 1-3, pages 1-3 and Conclusion, page 9). Ma et al. (Bioorg Chem 152, 2024) teach the efficacy of Cedrol and its derivatives for ameliorating rheumatoid arthritis via targeting the JAK3 pathway (see abstract).
25. The Level of Predictability in the Art: Despite the advanced training of those in the art, the pharmaceutical art is highly unpredictable. It is still not possible to predict the pharmacological activity or treatment efficacy of a compound based on the structure alone. Typically, in order to verify that a compound will be effective in a method or treating a disease, the compounds must be either tested directly in a patient or in a model that has been established as being predictive of efficacy. It is not predictable from the specification or from the prior art that the full scope of sesquiterpene derivative compounds of Chemical Formula 1 inhibit the expression of myostatin mRNA, or inhibit the expression of MURF1 mRNA, or inhibit the expression of Foxo3, in the cells of every subject for the treatment of sarcopenia, let alone prevention.
26. The level of detail required to satisfy the enablement requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. The fields of biology and chemistry are considered “unpredictable” because the complexity and unpredictability of chemical and biological interactions can make it difficult to understand the exact properties of an invention. In this case, a person of ordinary skill in the art from the Specification or from the prior art cannot predict the pharmacological effects of administration of the full scope of instant sesquiterpene derivatives of Chemical Formula 1 in a subject in regards to treatment or prevention of sarcopenia. The pharmaceutical industry is the prototypical example of a highly unpredictable field. Pfizer v. Teva Pharm., 482 F.Supp.2d 390, 413 (D.N.J. 2007); 2 Chisum on Patents § 5.04.
27. Once a compound has been identified by ligand based and/or structure-based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2).
28. This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised. This is certainly true in the case of Cedrol sesquiterpene derivatives which, as disclosed by Ma et al., demonstrate significantly altered activity following minor modifications, (see abstract, and IC50 values in Tables 1-3 at pages 7-10).
29. Regarding the predictability of treating sarcopenia, Lo et al. teach that “[t]hough the biological mechanism underlying sarcopenia is not clearly understood [10], there is a growing scientific and public interest to develop effective approaches to counteract the effects of sarcopenia to maintain functional independence or known as “active ageing”, (see page 39, left column, third paragraph). As such, one is treating the symptoms of sarcopenia, not preventing.
30. The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification teaches the preparation of 29 sesquiterpene derivative species encompassed by Chemical Formula 1 (pages 24-51). However, the Specification discloses the inhibitory activity of only two compounds, i.e., Compound 1-1 and Compound 1-2, on myostatin and MuRF1 expression in muscle cells (Examples 1-4), and the effects of Compound 1-2 on muscle strength of aging mice (Example 3).
31. Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation.” Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “the specification 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 (Fed. Cir. 1993) (emphasis added).
32. At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
33. Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims". Amgen, Inc, v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation.”
34. As to the first inquiry, as discussed above, the claims are drawn to sesquiterpene derivatives of Chemical Formula 1, which are alleged by the Specification to act as myostatin mRNA inhibitors, MURF1 inhibitors and/or Foxo3 inhibitors. Considering that Chemical Formula 1 encompasses hundreds of thousands of compound species, and potentially millions of compound species, it is evident that the claims are broad. Yet, as discussed above, the instant Specification discloses the activity of only two compound species encompassed by Chemical Formula 1 as recited by the claims (i.e., Compound 1-1 and Compound 1-2). As such, the claim is extremely broad with respect to the disclosure. The second inquiry is discussed in detail below.
35. Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of Chemical Formula 1, which are alleged by the Specification to act as myostatin mRNA inhibitors, MURF1 inhibitors and/or Foxo3 inhibitors. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of Chemical Formula 1 with respect to the disclosure since Chemical Formula 1 encompasses hundreds of thousands of compound species, and potentially millions of compound species, whereas the instant Specification discloses only two such compound species exerting the disclosed activity. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the hundreds of millions of compounds encompassed by Chemical Formula 1 would exert the alleged activity based on the limited disclosure of two active compounds. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme.
36. Furthermore, given the unpredictability of Cedrol sesquiterpene derivatives in particular, as evidenced by Ma et al., it is highly unpredictable whether any compound within the genus of compounds of Chemical Formula 1 identified by rational drug design based on the instant disclosure would, in fact, be usable to treat sarcopenia, let alone prevent. Whether the other compounds of Chemical Formula 1 (i.e., those not identified by rational drug design based on the instant disclosure) would be usable is even less predictable. As such, the only way to ascertain which of the hundreds of thousands, and potentially millions, of claimed compounds encompassed by Chemical Formula 1 are usable for treating sarcopenia, let alone preventing, based on the limited disclosure would require undue experimentation. And, the method of preventing or treating sarcopenia recited in claim 10 fails to define a distinct patient population, i.e., a subject in need thereof. Therefore, the recited method embraces administering a sesquiterpene derivative represented by Chemical Formula 1 to any subject, for any reason, which also requires undue experimentation. Thus, the only way one skilled in the art is enabled to use the entire scope of the claims based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure, and delete the term “preventing” in claims 4-13.
Claim Objections
37. Claims 1, 4, and 10-13 are objected to for containing a period in the middle of the claim.
(a) Claim 1, at page 2, line 5, contains a period after the term “heteroaryl group.”
(b) Claims 4, and 11-13 each contain a period in line 3, after the term “active ingredient.”
(c) Claim 10 contains a period in line 3, after the term “subject.”
Appropriate correction is required.
38. Claims 3 and 7 are objected to because the first four lines of each claim are verbose. It is suggested that claims 3 and 7 be rewritten as follows:
--The sesquiterpene derivative or the pharmaceutically acceptable salt thereof of claim 1, wherein the sequiterpene derivative represented by Chemical Formula 1 is selected from the group consisting of the following Chemical Formulas:…--.
Conclusion
39. Claims 1-13 are pending in the application. Claims 1-13 are rejected. Claims 1, 3, 4, 7 and 10-13 are also objected to. No claim is presently allowable.
40. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628