DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined
Status
The present office action is in responsive to August 19, 2022 Information Disclosure Statement and corresponding original disclosure documents
Claims 1-3 and 5-9 are pending, claim 2 is original, claims 1, 3, 5-8 are amended, claim 9 is new and claim 4 is cancelled in the above-identified application.
Priority
U.S. Pat. Appln. Ser. No.: 17/904,607, Filed: September 13, 2023 is a 371 Nat.’ l Stage entry of WO 2022/134043 A1 (i.e., PCT/CN2020/139547, Intern.’l Filing Date: December 25, 2020, Intern.’l Pub. Date: June 30, 3022)
Information Disclosure Statement
An Information Disclosure Statements (IDS) submitted on August 19, 2022, respectively are in compliance with the provisions of 37 CFR 1.97.
Accordingly, Information Disclosure Statements have been considered by the Examiner.
Claim Rejections - 35 USC § 112
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 1, 2, 5 and 8, respectively, are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd 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.
In general, the claims of the present invention fail to define the metes and bounds of the claimed invention due to use of indefinite, vague, ambiguous or unclear or poorly defined functional terms and/or language (i.e., such that exact scope of the claimed invention cannot be ascertained) without support from the specification within the claim itself. Claims must particularly point out and distinctly the claimed invention. Moreover, claims identified above also lack clarity, due to unnecessary use of repetitive and/or redundant terms.
Claims 1, 2, 5 and 8, respectively, are rejected for recitation of the broad term “nicotinohydrazide derivative”, which is indefinite as it is unclear, vague and ambiguous, because may refer to different compounds without specific structural definitions in the specification, failing to "particularly point out and distinctly claim" the invention, leaving the scope unclear to one skilled in the art. The examiner argues the term doesn't provide clear boundaries for what constitutes a valid derivative, making the claim indefinite, especially if the specification doesn't describe the types or structural features of these derivatives. Claim amendments are required to provide clarification, such as “a nicotinohydrazide compound of Formula (I) or a pharmaceutically acceptable salt thereof”.
Claims 2 and 8, respectively, are rejected for lack of clarity and antecedent basis and for being indefinite vague and ambiguous, such that the metes and bounds of the claimed invention are indeterminate for these following reasons:
It lacks antecedent basis in claim 2 for inclusion of the indefinite article “the” before the first recitation of the following word “steps” in the phrase “a method for preparing a nicotinohydrazide derivative which comprises the steps of” and further does not clarify the claimed preparation method by identifying the metes and bounds of the claimed invention by not providing a synthetic sequence steps by defining reactants and reagents in each step for the preparation of the product as exemplified in Figure 1:
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Applicants are requested to amend claim 2 accordingly to identify above-identified reaction conditions.
Claim 8 is rejected for lack of clarity and for being indefinite vague and ambiguous for recitation of the following phrase: where “the nicotinohydrazide derivative” or the pharmaceutically acceptable salt thereof has “an effect of enhancing a Glycine N- methyltransferase (GNMT)”, such that it is unclear and indeterminate as to what the metes and bounds of the claimed invention are these following reasons:
“the effect of enhancing" is vague and inherently ambiguous failing to particularly point out and distinctly claim"; i.e., e.g.,
it is a functional limitation without clear scope as it is a relative and subjective term:
it doesn't specify how much enhancement, what the outcome is (e.g., treating a disease), or the specific mechanism (structure/acts) for that enhancement, leaving the claim's boundaries unclear and potentially covering more than the inventor intended or disclosed, especially for a functional claim.
Applicants are requested to amend the claims to
to include specific parameters, a defined measurement method (e.g., "a method for enhancing GNMT activity by [specific steps] to achieve [specific result/threshold]"), or by pointing to specific supporting text in the specification that provides the necessary clarity; i.e., e.g., to recite language such as "administering a sufficient amount of [specific compound] to a subject to increase GNMT activity by at least X%") and/or provide arguments to explain the claim's scope as supported by the original filed disclosure.
To overcome these rejections, Applicants must amend the claims to provide clarity and specificity accordingly.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 1-3 and 5-9 are rejected under 35 U.S.C. 112(a), because the specification, while enabling for:
[A] Specific nicotinohydrazide compound of formula (I):
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or a pharmaceutically acceptable salt thereof ;
wherein:
each of X, Y and Z is one of N and CH,
at least one of X, Y and Z is CH,
at least one of X, Y and Z is N,
and R is one of OH and NH2.
[AltContent: textbox (K117, X= N ,Y =Z= CH, R = NH2)]exemplified by spec. examples:
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;
[B] Specific methods for preparation of nicotinohydrazide derivative; i.e., specifically N'-(1-
(pyridin-2-yl)ethylidene)-2-carbohydrazide
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DOES NOT reasonably provide enablement for:
[1] the entire broad scope of ANY or ALL nicotinohydrazide derivative(s) of a compound of Formula (I)
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; or a pharmaceutically acceptable salt thereof,
ANY or ALL stereoisomers thereof (i.e., as in claim 1) ;
[2] A method for preparing a nicotinohydrazide derivative, comprising the steps of: reacting an ethyl nicotinate with a hydrazine hydrate to form a carbohydrazide; and performing a condensation of the carbohydrazide with an acetylpyridine to form an N'-(1-(pyridin-2-yl) ethylidene) - 2-carbohydrazide (i.e., as in claim 1) ;
[B] A method for treating ANY or ALL cancer disease(s), which comprises: administering a pharmaceutical composition comprising an effective amount of a nicotinohydrazide derivative or, a stereoisomer thereof or a pharmaceutically acceptable salt thereof having a structure of formula (I) (i.e., as in claim 5) ;
Claim 5, wherein the nicotinohydrazide derivative, the stereoisomer thereof or the pharmaceutically acceptable salt thereof has an effect of enhancing a Glycine N- methyltransferase (GNMT). (i.e., as in claim 8)
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 the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
These factors include the following:
Scope Of The Claims
The scope and nature of the claims and invention involves:
The present invention relates to a nicotinohydrazide derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof having a structure of formula (I):
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wherein each of X, Y and Z is one of N and CH, at least one of X, Y and Z is CH, at least one of X, Y and Z is N, and R is one of OH and NH2.
Thus, the scope of claims is very broad.
The Nature Of The Invention and 3) Predictability In The Art.
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the 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).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Number Of Working Examples And 5) Amount Of Guidance Provided By Applicants.
Working examples in the instant specification are directed to
[A] 4 Compound Examples based on following genus
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One shown synthesis example directed to K-115 (i.e., in Figure)
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[B] Compound Screening against Assays defined in specification embodiments, highlights of which are shown below:
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[C] While the specification provides extensive information directed to only to the 4 nicotinohydrazide compounds identified therein as the K-series, which have been identified as GMNT inducers in the specification:
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corresponding intermediates and synthetic methods of making those compounds, determination of activity against, such as inhibition of liver cancer cell lines in invitro and in vivo studies in mice (i.e., Results Example 3), and GNMT Acts as a Tumor Susceptibility Gene (TSG) in Prostate Cancer and Pancreatic Cancer (i.e., Results Example 4),
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;
there are NO Additional compound derivatives (i.e., except for 3 K-series compounds), NO stereoisomers thereof or additional cancer diseases other than specific cancers taught therein
Regarding that described above, identification additional compounds, stereoisomers, etc. that may be useful for general cancer diseases or disorders cannot be simply willed into existence.
As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However...there is no evidence that such compounds exist...the examples of the '881 patent do not produce the postulated compounds...there is...no evidence that such compounds even exist.”
The same circumstance appears to be true here. Hence, applicants must show that renal disease or disorder treatment methods, associated PDE-1 inhibitors, corresponding data and other requirements yields all the desired effects of the claimed invention, other than those exemplified by the limited Experimental Example section of the present invention, such as in examples can be made and used for the stated purpose in all situations across the board, not just in animals, but also in human subjects or limit the claims accordingly.
Level of skill in the art.
An ordinary artisan in the area of drug development would have experience in screening chemical compounds for particular activities. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
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 that Applicants are not enabled for using broad scope of nicotinohydrazide derivatives of Formula (I) or pharmaceutically acceptable salt or stereoisomers thereof or corresponding pharmaceutical compositions, or treating any cancer disease or disorder; i.e., e.g.,
a person of ordinary skill in the art would have to engage in undue experimentation to identify all possible derivatives, stereoisomers, cancer diseases or conditions that meet this complex description without explicit guidance or representative examples in the specification.
"The specification does not teach how to treat all claimed conditions": The phrase covers a potentially vast number of different cancers and the specification does not provide sufficient data or teaching to show the claimed method works across the entire breadth of these diseases/conditions.
there are NO Prophetic Examples that are credible to enable a skilled person to practice the invention without undue experimentation to satisfy the enablement requirement.
Applicants are requested to amend the claims to be commensurate in scope with the enabled compounds or pharmaceutically acceptable salts thereof (i.e., specific compound species identified in the specification and not found in the prior art) and corresponding cancers selected from liver, pancreatic or prostate cancers.
Appropriate action is required accordingly in the instant application.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 5-6 are rejected under 35 U.S.C.103 as being unpatentable over WO 2018/017589 A1 (i.e., Intern.’l Filing Date: July 14, 2017 Intern.’l Pub Date: January 25, 2018), alone, in combination
with and/or in view of Madany et al., Discoveries (Craiova) 2018 Dec 31; 6(4): e86. doi: 10.15190/d.2018.7 and Ashikari et al., ABSTRACT Oncogene, 2017 Nov 9;36(45):6272-6281.
doi: 10.1038/onc.2017.225. Epub 2017 Jul 10.
The present invention is directed to a
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In general, WO ‘589 Appln. teaches and discloses the following invention, which reads on the claimed invention.
In particular, the WO ‘589 Appln. relates to:
a compound genus of Formula (I):
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or a pharmaceutically acceptable salt thereof,
which encompasses compounds of the claimed invention (i.e., see as discussed in greater detail below)); also teaches a compound of Formula (Ia), which reads on and anticipates the claimed invention:
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m = 0, n = 1 and R1 and R2 are as defined above and in the specification.
corresponding pharmaceutical compositions thereof (i.e., see specification and claim 18); and
Methods of treating a cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound as described above, or a pharmaceutically acceptable salt thereof (i.e., see abstract therein; and specification at page 30, lines 21-30, page 32, lines 7-14 to page 33, lines 1-4, page 33, lines 3-15, page 35, lines 1-30 to page 36, lines 1-5, etc.)
where with respect to each of the above:
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; and
Compounds of the WO ‘589 Appln. are identified as antagonists of G3BP2, G3BP1, and ZEB1. Pharmaceutical compositions comprising G3BP2 inhibitors, methods of inhibiting G3BP2, G3BP1, and ZEB1; and
Pharmaceutically compositions, acceptable excipients and carriers are defined in the WO ‘589 specification at page 29, lines 8-30 to page 30, lines 4-11.
While the WO ‘589 Appln. teaches:
use of compounds taught therein for the treatment of cancer and that
compounds taught therein are identified as antagonists of G3BP2, G3BP1, and ZEB1;;
pharmaceutical compositions comprising G3BP2 inhibitors, methods of inhibiting G3BP2, G3BP1, and ZEB1; and
it does not teach that:
Treated cancers may include those selected from the group consisting of a liver cancer, a prostate cancer or a pancreatic cancer and/or where liver cancer is hepatocellular carcinoma; or that
Nicotinohydrazide derivatives taught therein (and in the present invention) has an effect of enhancing a glycine N-methytransferase (GNMT).
However, G3BP2 and ZEB1 overexpression is known in the conventional art to be associated with increased malignancy in several cancers, most notably pancreatic, prostate and liver cancers (i.e., the later of would include hepatocellular carcinomas, as it is known as the most common type of primary liver cancer) as taught by the Madany and Ashikari references.
Based on the foregoing and the teachings of the art, the ordinary artisan in preparing nicotinohydrazide compounds or a pharmaceutically acceptable salt thereof, corresponding pharmaceutical compositions, preparation methods and/or methods for treatment of cancers (i.e., including, pancreatic, liver or prostate cancers) would meet with a reasonable expectation of success, because:
Nicotinohydrazide compounds known to demonstrate enhanced biological, chemical and/or physical properties as per chemical research (i.e., teaching chemical functional group modification on pyridine or hydrazide moieties/exploring chemical and biological activities to enhance or increased potencies); and
Given such research based on related compounds, one of ordinary skill in the art would have “good reason to pursue the known options within his or her technical grasp (i.e., see MPEP 2143: Section E “Obvious To Try”)”.
One of ordinary skill in the art would have been motivated to in preparing nicotinohydrazide derivative, or a pharmaceutically acceptable salt thereof, corresponding pharmaceutical compositions for use in methods for treatment of cancers (i.e., including, pancreatic, liver or prostate cancers), because the nicotinohydrazide moiety is conventionally known to in the art to:
exhibit a wide range of pharmacological activities, making it an attractive scaffold for developing new therapeutic agents;
with a structure known to have a nicotinohydrazide core that is known by skilled chemists to be modifiable (i.e., e.g., via linking with known anticancer agents or pharmacophores) in development of desired synergistic effects, improved efficacy, reduced side effects, low cytotoxicity to human cells, adaptable to target different biological pathways, etc.; and
There is a long-felt and unmet need for new, effective cancer treatments, providing a strong incentive for ongoing research into novel chemical entities like these derivatives.
Based on the foregoing, claimed invention is rendered obvious over the WO ‘176 Appln. alone, in view of or in combination with the teachings of the cited art references.
Conclusion
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to GRACE C HSU whose telephone number is (571) 270-1689. The Examiner can normally be reached Monday-Friday 7:30 am - 6 pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicants 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, Jeffrey H. Murray can be reached on 571-272-9023.
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/G.C.H./
Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624