DETAILED ACTION
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 the Claims
Claims 1, 2, 8, 9, and 11-18 are pending. Claims 3-7 and 10 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/CN2020/107028, filed on August 5, 2020. This application also claims the benefits of foreign priority to CN201910721525.7, filed on August 6, 2019.
Withdrawn Rejections
Applicant is notified that any outstanding rejection or objection that is not expressly maintained in this office action has been withdrawn or rendered moot in view of applicant’s amendments and/or remarks.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Menet et al. (Menet) (WO2010010190A1; published January 28, 2010).
Novelty:
Menet teaches [1,2,4]triazolo[1,5-a]pyridine compounds represented by formula (I) (herein, referred to as Menet-formula-I):
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as JAK inhibitors that are useful for the treatment of degenerative and inflammatory diseases (title, abstract, and para. 0001). The variables of Menet-formula-I are defined in claim 1 of Menet. The JAK inhibitors represented by Menet-formula-I (specifically, examples disclosed on pg. 115-194) differ from those presently claimed in that all the compounds of Menet do not have Cy1 = a thiophene moiety.
Thus, the instant invention is considered novel.
Nonobviousness:
Both Menet and the present invention disclose JAK inhibitors. Although a POSITA would have considered it obvious to further explore derivatives of the compounds disclosed in Menet (such as the compounds of the present invention) as JAK inhibitors, Menet does not teach nor suggest Cy1 of Menet-formula-I to be specifically a thiophene moiety to arrive at the instantly claimed compounds.
For example, compound 200 of Menet has the following structure (pg. 160):
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and instant compound EXP-1 has the following structure
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(instant specification, pg. 5)
The only structural difference between the two compounds is that the instant compound EXP-1 replaces the phenyl linker present in compound 200 of Menet with a thiophene moiety. Although Menet states in claim 1 that Cy1 (which corresponds to phenyl in compound 200 of Menet) may be an aryl or heteroaryl (which includes a thiophene moiety), Menet does not teach nor suggest that a POSITA would have been motivated to specifically select thiophene over the numerous other disclosed aryl and heteroaryl groups to achieve the improved and unexpected results demonstrated in the instant specification.
Thus, the instant invention is considered nonobvious.
Claim Objections
Claim 1 is objected to because of the following informalities:
In claim 1: “F, Cl and B;” should read “F, Cl and Br;”
Appropriate correction is required.
Maintained Rejections
Claim Rejections - 35 USC § 112(a) - 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 2 and 8 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims a JAK kinase inhibitor represented by formula I
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or a stereoisomer or tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate thereof. Further, the use of the compound of formula I in preparation of drugs for treating JAK kinase-related diseases, especially in preparation of drugs for treating diseases involving cartilage degradation and bone and/or joint degradation, conditions involving inflammation or immune response, endotoxin-driven disease states, cancer, and organ transplantation rejection.
The variables of formula 1 are defined in instant claim 1.
State of the prior art
See “Examiner’s note on novelty and nonobviousness” section above.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples; the amount of direction or guidance present; and the quantity of experimentation necessary
The quantity of experimentation needed to make or use the invention must be considered to determine if undue experimentation is present. With regard to quantity of experimentation needed, (note Wolff et. al., "Burger's Medicinal Chemistry and Drug Discovery," 5th Ed. Part 1, pp. 975-977 (1995) provided with this action), which emphasizes the many experimental factors for consideration for a successful prodrug as well as the difficulty in extrapolating data from one species to another. See p.975-977. “Extensive development must be undertaken to find the correct chemical modification for a specific drug. Additionally, once a prodrug is formed, it is a new drug entity and therefore requires extensive and costly studies to determine safety and efficacy.” Banker, et. al., (1996), Modern Pharmaceutics, p.596, section “B. Prodrugs”, last paragraph. In view of all these factors undue experimentation would be required to practice the invention.
The scope of prodrugs is not adequately enabled or defined. Applicants provide no guidance as how the compounds are made more active in vivo nor do they provide any working examples of suitable prodrugs. The choice of a prodrug will vary from drug to drug. Therefore, more than minimal routine experimentation would be required to determine which ester, for instance, will be suitable for the instant invention. The application does not provide any guidance for one skilled in the art on how the prodrug is converted to active compounds, by what mechanisms and at what site the prodrug will be activated, what in vivo enzymes are likely involved in cleaving the protected group, etc.
Applicants provide no reasonable assurance that any and all known prodrugs will have the ability to regenerate in vivo to the instant compounds by one or more biological processes. It is not the norm that one can predict with any degree of accuracy a particular prodrug form of an active compound will be more soluble, more easily handled in formulations or more bioavailable without actual testing in vivo. Pursuant to In re Wands, 8 USPQ2d 1400, factors such as direction or guidance are not seen in the specification.
Many functional groups (e.g., hydroxy, amino groups) present in drugs are capable at least in theory to being derivatized but determining what is a prodrug and what is not requires knowledge of an intended effect (i.e. modification of an undesirable property in the parent drug- poor solubility, poor bioavailability, poor shelf-life) which is never identified by the specification.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 8 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.
Claims 2 and 8 recite “prodrug.” The term “prodrug” renders claims 2 and 8 indefinite as a prodrug does not have a defined structure known in the art. For example, one would not be apprised of the pharmacologically inactive form of the claimed compound from the simple recitation of “prodrug” as the compound itself has multiple sites to which a prodrug moiety could bind. Moreover, one could not ascertain as to which prodrug moieties are within the scope of the claim, resulting in millions of combinations of prodrug moieties associated with the claimed compound at different locations on its structure. One could not possibly envisage all the possibilities of a prodrug of any compound of the instant invention.
Rejections necessitated by the amended claims
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 13-18 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 comprising preparing drugs for treating diseases involving cartilage degeneration and bone and/or joint degeneration with the compound according to claim 1, 2, or 8 and
A method comprising preparing drugs for treating rheumatoid arthritis, osteoarthritis, psoriasis, juvenile idiopathic arthritis and/or a disease with cartilage renewal damage, congenital cartilage deformity, cartilage degeneration, and/or joint degeneration with the compound according to claim 1, 2, or 8
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
See “1. The nature of the invention” section in “Claim Rejections - 35 USC § 112(a) – Enablement” from the “Maintained Rejections” section above.
State of the prior art
See “Examiner’s note on novelty and nonobviousness” section above.
The level of the skill in the art
See “3. The level of the skill in the art” section in “Claim Rejections - 35 USC § 112(a) – Enablement” from the “Maintained Rejections” section above.
The presence or absence of working examples; the amount of direction or guidance present; and the quantity of experimentation necessary
The instant specification provides a working example of instant compound EXP-3 in a rat model of collagen-induced arthritis (CIA) to assess the compound’s efficacy in treating arthritis in rats (Embodiment 18: Pharmacodynamics model in vivo starting on pg. 48). The test results show that a 10 mg/kg dose of EXP-3 (administered for two weeks) has the strongest effect on reducing swelling of the extremities of the rat subjects (pg. 51, Table 11). According to the prior art, CIA is an established experimental model of human rheumatoid arthritis (RA) as the CIA model is “suitable for studying the alterations of immune functions during [RA] disease development and progression” (Richter, J. et al. Collagen-induced arthritis: severity and immune response attenuation using multivalent N-acetyl glucosamine. Clinical and Experimental Immunology 2014, 177, 121–133.; pg. 122, left col., 2nd paragraph).
Based on these teachings, instant compound EXP-3 will have utility for treating RA. However, there is no teaching either in the specification or the prior art stating that compounds having efficacy in a rat model of CIA are well known to have therapeutic utility for treating:
any condition involving any inflammation or immune response, any endotoxin-driven disease states, any cancer, and any organ transplantation rejection or
more specifically, Crohn’s disease, allergic airway disease, colitis, inflammatory bowel disease, myeloproliferative disorder, leukemia, and solid tumor.
While Applicant does report of tests that were run to detect the instant compounds’ proliferation inhibitory activity on HeLa cells (Embodiment 12-1, pg. 42), BaF3 cells (Embodiment 12-2, pg. 43), and THP1 cells (Embodiment 12-3, pg. 44), there are no working examples demonstrating the efficacy of instant compounds in animal models for the treatment of any cancer.
In the absence of such guidance and working examples, it would require undue experimentation to demonstrate efficacy of the instant compounds in the treatment of the aforementioned diseases and/or conditions. Therefore, the instant specification does not fully enable claims 13-18.
The breadth of the claims
The claims are broad insofar as the instant claims recite a method comprising preparing drugs for treating a variety of diseases and/or conditions.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 13-18 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.
Claim 2 reciting the limitation "prodrug" renders the claim indefinite as there is insufficient antecedent basis for this limitation in the claim. Claim 2 is dependent on claim1 which does not mention that the compound of formula (I) can be in the form of a prodrug.
Claims 13-18 recite “A method comprising preparing drugs…” with the compound according to claim 1, 2, or 8; however, the claims fail to recite any operative method steps for preparing the drugs. As a result, the scope of the claimed method cannot be determined with reasonable certainty, and the metes and bounds of the invention are indefinite.
Allowable Subject Matter
Claim 1 is currently objected to but would be allowable once appropriate corrections are made. Claim 9 is currently objected to for being dependent upon an objected claim (i.e., claim 1) but would be allowable once appropriate corrections are made to claim 1.
Claims 11 and 12 are currently objected to as being dependent upon a rejected base claim (i.e., claims 2 and 8, respectively), but would be allowable once the rejections set forth for claims 2 and 8 are overcome.
Conclusion
Claims 1, 9, 11, and 12 are objected to. Claims 2, 8, and 13-18 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624