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 .
Status of Claims
Claims 1-20 are pending in the instant application.
Domestic Benefit
The instant application claims domestic benefit to US Provisional Application No. 63/126,332, filed on December 16th, 2020. Claims 1-20 are fully supported by this application, and will be evaluated with an effective filing date of December 16th, 2020.
Information Disclosure Statement
The Information Disclosure Statement filed January 10th, 2025 has been fully considered by the examiner, except where marked with a strikethrough.
Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which Applicant may become aware of in the specification.
Claim Objections
Claim 16 is objected to because of the following informalities: Claim 16 is drawn to a finite set of chemical compounds. However, Claim 16 defines these compounds by referencing the specification. Per MPEP 2173.05(s), “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).” Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-15 and 17-20 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 compound of Formula (I) as recited in instant Claim 1 in which when R4 and R5 are defined according to (AA), R4 is C1-15 alkyl optionally substituted with 1-6 Ra or –(YA1)nYA2 wherein n is 0 and YA2 is any of the recited groups other than C3-10 cycloalkyl or C3-10 cycloalkenyl, R5 is H, R6 is CN wherein m=1; Y1 is CR1a, Y2 is CR2a, Y3 is CR1c, X1 is N(R2) wherein R2 is H, X2 is CR1e wherein R1e is H, and X3 is CR1f, wherein R1f is H does not reasonably provide enablement for compounds of Formula (I) as recited in instant Claim 1 where these variables are otherwise defined. 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.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to a compound of the formula:
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or pharmaceutically acceptable salts thereof.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to any compound of the formula noted above, allowing for myriad combinations of the variables recited thereof.
State of the prior art and 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 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.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis 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 be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
The compound core depicted with specific substituents represents a narrow subgenus for which applicant has provided sufficient guidance to make and use; however, the disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working example of any compound or pharmaceutically acceptable salts thereof where R4, R5, Y1, Y2, Y3, X1, X2, and X3 were not defined as noted above in the instant application.
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims.” Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
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 UPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here that Applicant is not enabled for making these compounds.
Claim 20 is 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.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to a method of treatment of disease, disorder, or condition associated with STING.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to the treatment of any disease, disorder, or condition associated with STING by administering any of the numerous compounds of Formula (I) as recited in Claim 1. This could cover an array of diseases, disorders, or conditions, both known presently, or diseases, disorders, or conditions that are not yet known, but are discovered years from now to have an association with STING. Can the Applicant simply “reach through” and obtain patent protection for diseases, disorders, or conditions that have yet to be discovered, or for diseases, disorders, or conditions presently known, but are later discovered to have an association with STING? Further, the instant specification states at Page 56, Last Paragraph, and Page 57, first paragraph that the condition, disease, or disorder is cancer. This is an incredibly broad genus that includes a myriad of species of cancer with mutually exclusive and distinct etiologies.
State of the prior art and predictability in the art:
No compound has ever been found to treat cancers of all types generally. Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. The existence of such a “silver bullet” is contrary to our present understanding of oncology. The state of the art is not indicative of any pharmaceutical agents that are useful in the treatment of cancer generally. At Page 1004, Cecil Textbook of Medicine states that “each specific type has unique biologic and clinical features that must be appreciated for proper diagnosis, treatment and study”. Different types of cancers affect different organs and have different methods of growth and harm to the body. Also see In re Buting, 163 USPQ 689 (CCPA 1969), wherein ‘evidence involving a single compound and two types of cancer, was held insufficient to establish the utility of the claims directed to disparate types of cancers’. Thus, it is beyond the skill of oncologists today to get an agent to be effective against cancers generally.
A similar statement appears at In re Application of Hozumi et. al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body’s cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environmental factors.
Similarly, In re Novak, 134 USPQ 335, 337-338 says “unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them.” There is no such evidence in this case for a compound that treats all types of cancer. Likewise, In re Cartright, 49 USPQ2d 1464, states: “Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient” does what the specification surmises that it does. That is exactly the case here. Moreover, even if Applicant’s assertion that cancer in general could be treated with these compounds were plausible -- which it is not --, that “plausible” would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.
Recently, Wu et. al. (“Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA- approved novel therapeutic drugs for solid tumors from 1991 to 2021; Journal of Hematology & Oncology, 15, 143, 2022; hereinafter referred to as Wu), at the Abstract, discloses that between 1991 and 2021 there have been 228 new cancer drugs approved by the U.S. Food and Drug Administration of which 120 of these are drawn to the treatment of solid tumors alone. At Page 5, Table 1 Wu teaches that there are 21 different approved drugs for treating lung cancers, some of which have cellular targets. At Page 10, Table 2, Wu teaches breast cancer has 22 different drugs that have varied cellular targets and are indicated for different types of breast cancer. At Page 17, Table 4, Wu teaches there are 17 different drugs available to treat different forms of gastrointestinal cancers. At Page 38, Figure 12, Wu summarizes the protein structure of some cellular targets and the binding site of their respective drugs. Taken together, Wu teaches that no single therapeutic has ever been identified as a treatment for all forms of cancer; and closer examination of Figure 12 provides a logical explanation. As highlighted in Figure 12, molecular protein targets implicated in different cancers (e.g. EGFR for lung cancer in Table 1, VEGFR2 for gastric cancer in Table 4) have different three-dimensional protein structures, different active sites, and therefore require different drugs with the right shape and chemical groups in order to bind the target active site and have an effect in treating cancer. In other words, there is no one size fits all approach to treating cancer simply for the reason that no single molecule will have the shape and chemical functional groups necessary to bind and modulate all modular targets of cancer, all of which have varied shapes. It is commonly known in the pharmaceutical arts that shape dictates function wherein drugs which have a shape complimentary to the protein target will bind and have an effect (this is often referred to simplistically as a “Lock and Key” model). Given the varied shape of protein targets in cancer (e.g. EGFR and VEGFR2), it is pure fantasy to speculate that a single drug with a single three dimensional shape will bind all protein targets implicated in cancer therapy and have an effect in treating all forms of the disease. As such, at present the “silver bullet” drug therapy to treat all forms of cancer is elusive and such a therapy is not recognized in the art where the reality is that different forms of cancer require different drug therapies.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis 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 be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
Beginning at Page 111 of the instant specification, Applicant sufficiently discloses the protocol for a luciferase reporter assay employed to determine EC50 values of the instantly claimed compounds, sufficiently enabling the instant disclosure for the activity of the instantly claimed compounds against hSTING.
No examples have been provided, however, that demonstrate the efficacy of administration of the disclosed compounds in treating a disease, disorder, or condition. The provided examples are not sufficient to extrapolate efficacy of the disclosed compounds in treating a disease, disorder, or condition associated with STING.
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. A person having ordinary skill in the art would need to not only identify and/or develop methods to evaluate the efficacy of the instantly claimed compounds in treating a disease, disorder, or condition, but also to employ these metrics, with no assurance of success. In other words, the limited assay data provided is not sufficient to guide a person having ordinary skill in the art to understand which diseases, disorders, or conditions are suitable for treatment by the instantly claimed method.
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.
Genentech Inc. v Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person having ordinary skill in the art would have to engage in undue experimentation to determine which diseases, disorders, or conditions are suitable for treatment by the instantly claimed compounds, with no assurance of success.
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.
Claim 19 is 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 19 recites the limitation of “a method of inducing an immune response in a subject in need thereof.” The instant specification does not provide any indication as to the metes and bounds of such an immune response, nor is a subject in need thereof sufficiently defined that it would be readily understood by a person having ordinary skill in the art. Appropriate clarification is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Berry et. al. (WO 2016/176460; cited on Applicant’s Information Disclosure Statement filed January 10th, 2025; hereinafter referred to as Berry).
At Page 232, Berry teaches the compound N4-(2-Fluoroethyl)-N4-methyl-N2-(7-methyl-1H-indazol-5-yl)-3-nitro-6-(trifluoromethyl)pyridine-2,4-diamine. This compound has the structure:
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This compound reads on a compound of Formula (I) when the variables are defined as follows:
R4 and R5 are defined according to (AA), wherein R4 is C2-alkyl, substituted with one Ra, wherein Ra is -halo wherein -halo is fluoro and R5 is Rd, wherein Rd is C1 alkyl.
m is 2, wherein one R6 is Rc, wherein Rc is NO2, and the second R6 is Rc, wherein Rc is C1 alkyl substituted by three Ra, wherein each Ra is halo, wherein halo is fluoro.
R3 is H.
Y1 is CR1a, wherein R1a is H.
Y2 is CR1b, wherein R1b is H.
Y3 is CR1c, wherein R1c is Rc wherein Rc is C1 alkyl.
X1 is N(R2), wherein R2 is H.
X2 is N.
X3 is CR1f, wherein R1f is H.
Regarding Claim 2, this compound reads on a compound of Formula (I-a1) when the variables are defined as above.
Regarding Claim 3, this compound reads on a compound of formula (I-a1-a) whenm1 is defined as 1, and the rest of the variables are defined as above.
Claims 1-2, 4, 7, 9-11, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nair et. al. (“Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis”, ACS Med Chem Lett, 2020, 11, 1402-1409; cited on Applicant’s Information Disclosure Statement filed January 10th, 2025; hereinafter referred to as Nair).
At Page 1403, Figure 1, Nair teaches the following compound as Compound 3:
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This compound reads on a compound of Formula (I) as recited at instant Claim 1 when the variables are defined as follows:
R4 and R5 are defined according to (AA), wherein R4 is C3 alkyl and R5 is H.
m is 1.
R6 is Rc. wherein Rc is -C(=O)NR’R’’, wherein R’ is H and R’’ is methyl.
R3 is H.
Y1 is CR1a, wherein R1a is H.
Y2 is CR1b, wherein R1b is H.
Y3 is CR1c, wherein R1c is H.
X1 is S.
X2 is CR1e, wherein R1e is H.
X3 is N.
Regarding Claim 2, this compound reads on a compound of Formula (I-a1) when the variables are defined as above.
Regarding Claim 17, at Page 1403, Figure 3, several IC50 values are reported for various assays for Compound 3. A person having ordinary skill in the art would recognize that a pharmaceutical composition comprising Compound 3 would have been administered to acquire these IC50 values.
Claims 1-2, 4, 7, 9-11, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bhide et. al. (“Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors”, Bioorganic & Medicinal Chemistry Letters, 27, 4908-4913, 2017; cited on Applicant’s Information Disclosure Statement filed January 10th, 2025; hereinafter referred to as Bhide).
At Page 4910, Table 3, Bhide teaches compounds of the structure:
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The compounds in this table read on a compound of Formula (I) as recited at instant Claim 1. For example, Compound 16, which defines both R and R1 in the above formula as methyl reads on a compound of Formula (I) when the variables are defined as follows:
R4 and R5 are defined according to (AA), wherein R4 is C1 alkyl and R5 is H.
m is 1.
R6 is Rc, wherein Rc is -C(=O)NR’R’’, wherein R’ is H and R’’ is C1 alkyl.
R3 is H.
Y1 is CR1a, wherein R1a is H.
Y2 is CR1b, wherein R1b is H.
Y3 is CR1c, wherein R1c is H.
X1 is S.
X2 is CR1e, wherein R1e is H.
X3 is N.
Regarding Claim 2, this compound is a compound of Formula (I-a1) when the variables are defined as above.
Regarding Claim 17, at Page 4910, Table 3, several IC50 values are reported for various assays for Compound 3. A person having ordinary skill in the art would recognize that a pharmaceutical composition comprising Compound 3 would have been administered to acquire these IC50 values.
Conclusion
Claims 1-15 and 17-20 are rejected.
Claim 16 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL JOHN BURKETT whose telephone number is (703)756-5390. The examiner can normally be reached Monday - Friday.
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/D.J.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624