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
The instant application was received 11 October 2024; it is a national stage application of PCT/CN2023/088006, filed 13 April 2023, and claims foreign priority to CN202310279357.7, filed 21 March 2023, and CN202210385527.5, filed 13 April 2022. Acknowledgment is made of Applicant’s claim for foreign priority and certified copies of the priority documents have been received.
Status of the Claims
The listing of claims filed 11 October 2024 has been examined.
Claims 1-17 and 19-21 are pending.
Claims 1-7 and 9-17 are amended.
Claims 19-21 are newly added.
Claim 18 is cancelled.
Claims 1-17 and 19-21 are examined on the merits.
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed on 16 October 2024 is acknowledged and has been considered.
Claim Objections
Claims 1-4 are objected to because of the following informalities:
Claim 1 recites, “…the L, G, and R1 are optionally substituted by one or two or more independently selected from the group consisting of…” The word “groups” appears to be missing. Accordingly, Examiner suggests amending to, “…the L, G, and R1 are optionally substituted by one or two or more groups independently selected from the group consisting of…” [Emphasis added.] or similar. Claims 2-4 appear to have the same issue.
Appropriate correction is requested.
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 1-17 and 19-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP 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. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”) Thus, an applicant complies with the written description requirement “by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966,” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed genus is sufficient. See MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
In the instant case, the claims in the instant application embrace compounds represented by formula (I) as well as, “…a stereoisomer, tautomer or mixture form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof…” [Emphasis added.] Particularly, the term “prodrug”, recited in claims 1-17 and 19-21, invokes the 35 U.S.C. 112(a) rejection. Even a cursory calculation of the number of compounds embraced in the instant claims would result in thousands of compounds.
Level of Skill & Knowledge in the Art
The level of skill and knowledge in the art is high.
Partial Disclosure
Compounds represented by formula (I) have been disclosed and example compound species that would be within the general formula have been disclosed. However, as to the claimed prodrugs, no specific examples are given that would demonstrate possession or put the public in possession of all the claimed prodrugs of formula (I). It is generally accepted that prodrugs may vary by chemical formulae and may also differ in properties and the arrangement of atoms in the molecule.
Physical and/or Chemical Properties/Functional Characteristics
The compounds represented by formula (I), and prodrugs thereof, are compounds which are allegedly useful in methods for treating or preventing a disease associated with 15-PGDH (Claim 20). Although the art recognizes generally accepted definitions, the term “prodrug” is not explicitly defined by the Specification in such a way as to demonstrate that the inventors had possession of the prodrug of formula (I).
A review of the prior art identifies Najjar (Anas Najjar & Rafik Karaman (2019) Successes, failures, and future prospects of prodrugs and their clinical impact, Expert Opinion on Drug Discovery, 14:3, 199-220), which discloses successes and failures of prodrugs of known pharmaceuticals (p. 212, 3. Previous failed prodrugs). Najjar teaches hetacillin, an ester prodrug of ampicillin, which was withdrawn since it did not have a superior advantage when compared to ampicillin. In light of Najjar, it is unknown which of the prodrugs of compounds of formula (I) claimed by Applicant will be active or inactive. Further, one of ordinary skill in the art would not be able to predict which compounds, of the vast number that are claimed, will be active or inactive absent evidence. There is no structure/function correlation in the Specification showing which prodrugs would or would not be active.
Since Applicant has not set forth compounds or substituents on formula (I) in the Specification which Applicant considers prodrugs, it is not clear what compounds fall under formula (I). Applicant has not described which prodrugs have the ability to treat or prevent a disease associated with 15-PGDH and which prodrugs lack said ability. Stated differently, there is no structure/function correlation and no representative number of specific examples of prodrugs that demonstrate which compounds retain activity. Further, one or ordinary skill in the art would not be able to predict the biological activity of the claimed prodrugs of formula (I).
Predictability of the Art
Medicinal chemistry is an experimental science with a low predictability level. Small changes in the structure of a compound can lead to large differences in their pharmacological activity. Regarding prodrugs, predicting if a certain claimed compound retains the activity and function of the original drug is filled with experimental uncertainty because prodrugs contain variation by chemical and physical properties of the molecules.
Method of Making the Claimed Invention
Although the Specification provides methods for making compounds of formula (I) (p. 27, ¶ [0090]), no method for making all of the compounds, including prodrugs, encompassed by the instant claims has been disclosed. Methods of synthesizing compounds are, in general, known to a person of ordinary skill; however, methods of making the myriad of compounds encompassed by the instant claims is beyond the skill of the artisan, particularly when certain elements, such as prodrugs, are merely described partially.
As such, the instant Specification and instant claims do not provide sufficient description such that one could anticipate what additional elements may be present in the prodrugs of formula (I) because the examples illustrated in the experimental section are limited to only compounds of formula (I).
Written Description Conclusion
Substantial and undue experimentation would be needed to practice Applicant’s invention because the Specification lacks sufficient detail to show how to use the prodrugs of the instant invention. Further, there is no guarantee that all of the prodrugs embraced by the scope of the claims would be useful in methods for treating or preventing a disease associated with 15-PGDH.
Even with the undue burden of experimentation, there is no guarantee that one would obtain the product of a desired prodrug of an instant compound of formula (I). Although some functional characteristics are disclosed or would be known to a person of ordinary skill in the art, in the absence of a disclosed structure, there can be no correlation between the function and structure of the claimed prodrugs in the instant application.
The MPEP states that written description for a genus can be achieved by a representative number of species within a broad genus. It is unquestionable that the claims are broad and generic with respect to all possible compounds encompassed by the claims. In other words, the possible structural variations are limitless to any prodrugs of the genus. In the instant case, however, the Specification does not disclose a sufficient variety of species to reflect this variance in the genus. The Specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims, such as prodrugs of formula (I).
The description requirement of the patent statute 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 inventors, at the time the application was filed, had possession of the entire scope of the claimed invention. This rejection would be overcome by amending the claims to remove the term, “prodrug”.
Claims 20-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because 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.
Claim 20, upon which claim 21 depends, recites, “A method of treating or preventing a disease associated with 15-PGDH, comprising administering to a subject in need thereof the compound… according to claim 1, or a pharmaceutical composition thereof.” This is a broad genus and, according to its broadest reasonable interpretation, includes any 15-PGDH-associated disease. While the Specification, in view of the prior art, reasonably provides enablement for the treatment of diseases associated with 15-PGDH, it does not reasonably provide enablement for the prevention of diseases associated with 15-PGDH or the treatment or prevention of all diseases associated with 15-PGDH encompassed by claims 20-21.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or 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.
The Wands factors are analyzed with respect to the claimed elements in turn below.
The breadth of the claims and b) the nature of the invention. The claims are directed to a method of treating or preventing a disease associated with 15-PGDH, said method comprising administering to a subject in need thereof the compound, the stereoisomer, tautomer or mixture form thereof, or the pharmaceutically acceptable salt thereof, or the solvate thereof, or the prodrug thereof according to claim 1 (Claim 20).
The range of diseases that can be associated with 15-PGDH is extensive. For example, some instantly recited 15-PGDH-associated diseases include gum disease, skin damage, hair growth, and eye disease (Claim 21). As such, the scope of the claims is broad.
The state of the prior art. This can be ascertained by reviewing the Background of the Specification and relevant literature. The instant Specification states, “Receptors of 15-PGDH substrates are widely and differentially distributed in vivo, and the diversity of expression distributions, receptor types, and signaling together create a diversity of functions in vivo.” (p. 1, ¶ [0003]).
A review of the prior art identifies Sun (C.-C. Sun et al. (2021) Recent advances in studies of 15-PGDH as a key enzyme for the degradation of prostaglandins, International Immunopharmacology, 101, 108176). Sun states, “…recent research shows that 15-PGDH plays an important role in the development of inflammation, fibrosis, and cancer-related diseases.” (p. 1, Col. 2, Lines 3-5).
The level of one of ordinary skill. This may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
The level of predictability in the art. Pharmacology is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 CJ ¶3). Similarly, it is well established that [T]he scope of enablement varies inversely with the degree of unpredictability of the factors involved, and physiological activity is generally considered to be an unpredictable factor {See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970)}.
The amount of direction provided by the inventor and g) the existence of working examples. The amount of guidance 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. The less predictable the nature of the invention, the more information needs to be explicitly stated in the Specification. See MPEP 2164.03.
The Specification indicates a “pharmaceutical composition” may include additional components like physiologically/pharmaceutically acceptable carriers and vehicles (p. 25, ¶ [0078]) and provides working examples related to synthesis methods (p. 27, ¶ [0090]) as well as in vitro biological data (p. 60, ¶ [0240]; p. 63, ¶ [0247]). However, there are no working examples demonstrating the in vivo activity of the claimed compounds of formula (I) of their efficacy in preventing 15-PGDH-associated diseases. For example, claim 21 indicates “skin damage” is a 15-PGDH-associated disease. Skin damage can be caused by sunburn or skin lacerations, both which could be considered diseases “associated with 15-PGDH” due to the role of 15-PGDH in the inflammatory response (p. 1-2, ¶ [0003]). Based on the Specification, it is unclear how administering the instantly claimed compounds would prevent sunburn or skin lacerations.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure. The treatment or prevention of a disease associated with 15-PGDH would depend at the very least on the cause of said disease (i.e., chemical or physical) and the developmental stage of the subject (i.e., infant, adult, etc.).
In order to practice the invention commensurate with the full scope of the claims, the skilled artisan would need to undertake experiments in order to determine (1) whether the compound is, in fact, clinically useful for the treatment of the claimed diseases; (2) the amount of the compound that is to be administered; (3) the frequency of dosing and the manner in which the compound is to be administered; (4) the likely side effects and how they should be mitigated; and (5) the pharmaceutical formulation that is suitable for administration to a patient.
Scope of Enablement Conclusion
In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a PHOSITA to use the full scope of the claimed invention. While the state of the art does agree that 15-PGDH activity has been implicated in various diseases, claims 20-21, as written, capture too broad a scope. Given the level of unpredictability in this technology area, and the relative lack of working examples or other specific guidance or teachings by Applicant, Examiner concludes that one skilled in the art would be burdened with undue experimentation when attempting to practice the full scope of the invention as claimed. Deleting the word “preventing” from claims 20-21 would overcome the rejection.
Allowable Subject Matter
Claims 1-17 and 19-21 contain allowable subject matter. None of the prior art of record nor a search in the pertinent art area teaches a compound represented by formula (I).
The following is a statement of reasons for the indicated of allowable subject matter:
The instant application claims compounds represented by formula (I), shown below:
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145
255
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The closest prior art is Markowitz (CN 110573154 A; IDS dated 16 October 2024, Cite No. C2). Shown below are exemplary compounds disclosed by Markowitz (p. 5, Col. 2, Bottom Row; p. 7, Col. 3, Middle Row), which share some structural similarities to the instantly claimed compounds:
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78
119
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151
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The instantly claimed compounds differ from Markowitz in the following respects:
In the instantly claimed compounds, the core structure comprises a tricyclic heterocycle. However, although Markowitz also discloses compounds which are 15-PGDH modulators, in the compounds disclosed by Markowitz, the core structure comprises a bicyclic heterocycle. Markowitz fails to disclose any exemplary compounds which comprise a tricyclic heterocycle.
Thus, while Markowitz’s compound shares some structural similarities with the instantly claimed compounds having a structure of formula (I), a skilled artisan would not have been motivated to make the aforementioned changes as a whole to the structures which would have resulted in compounds having a structure of formula (I).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANNA L BAUER whose telephone number is (571)272-5752. The examiner can normally be reached 8am-5pm.
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/B.L.B./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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