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 .
Application and Claims Status
Applicant’s preliminary amendments filed on January 31, 2024 are acknowledged and entered.
Claims 1-13 were pending. In the amendment as filed on January 31, 2024, applicants have amended claims 3-13; cancelled no claims; and added new claims 14-15. Therefore, claims 1-15 are currently pending. Additionally, the present specification is amended in order to cross reference to related applications and properly claim priority, as well as add the inventors’ names after the title.
Priority
The instant application is a National Stage of International Patent Application No. PCT/CN2022/100186, filed on June 21, 2022, which claims priority to Chinese Patent Application No. 202110685264.5, filed on June 21, 2021, both of which are incorporated herein by reference in their entireties.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 1/31/2024; 10/23/2024; 05/06/2025 are all in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action.
Specification – Disclosure
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 1 is objected to because of the following informalities: in the limitation of R1 and R2, applicant recites “…and halogen,; and…” and adds an additional comma between “halogen” and the semicolon; in the limitation of L, applicant misspells “independently” as “indepdnently”; the definition of R5a should be on a new line and indented, on page 4, in the definition of R5; in the limitation of X, for clarity, there should be dashes before and after the linking elements, as in “-O-, -S- or -(NR4)-“ (see instant claim 3, where it is done correctly). Appropriate correction is required.
Claims 1-15 are objected to because of the following informalities: the claim is not consistent with proper Markush practice. The claims should be listed in the singular alternative format. In the preamble of claim 1, for example, applicant includes the plural form and recites, “a tautomer thereof or a mixture of various isomers” and needs to be rewritten so as to be consistent with proper Markush practice. In another example, in claim 11, applicant recites “…one or more pharmaceutically acceptable carriers, adjuvants, or excipients” and examiner suggests that the claim be rewritten to read “one or more pharmaceutically acceptable carrier, adjuvant, or excipient”. In another example, in claim 12, applicant recites “a method for treating diseases or conditions...is selected from…” and examiner suggests that the claim be rewritten to read “a method for treating a disease or a condition…”. Appropriate action is required.
Claims 1-11, 13, and 15 are objected for their use of non-standard Markush claim language. Markush claims are commonly formatted as “selected from the group consisting of A, B, and C” or “wherein R is A, B, C, or D”. In claim 1, as an example, applicant recites “…wherein R1 and R2 are each independently selected from H, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and halogen…” Proper Markush claim language could optionally recite “…wherein R1 and R2 are each independently selected from the group consisting of H, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and halogen…” or ““…wherein R1 and R2 are each independently H, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or halogen…” As claims 2-11 depend upon claim 1 and either have the same problems or do not resolve the problems of claim 1, they are also rejected. Furthermore, claims 13 and 15 are rejected for their use of improper Markush claim language as it is applied to the list of diseases or conditions associated with TRK kinases or NTRK genes. Relevant guidance can be found in the MPEP § 2173.05(h), titled “Markush Claims,” which deals with claims that list alternatives.
Claims 12-15 are objected to over the use of the abbreviation “TRK” and “NTRK”. While “TRK” and “NTRK” have been specifically defined in the specification (page 1, para 0002-0003), applicant is encouraged to amend at least the first occurrence of this term in each string of independent/dependent claims to reflect the full meaning of the term and to more accurately describe applicants’ claimed invention.
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 1-15 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 1-12 recite “a prodrug thereof”. The term “prodrug” renders claims 1-11 indefinite as a prodrug does not have a defined structure known in the art. The instant specification defines a “prodrug” (pages 6-7, para 0021) as “a derivative that is converted into a compound according to the present disclosure by a reaction with enzymes, gastric acid, and the like in a living body under physiological conditions, for example, through oxidation, reduction, hydrolysis, and the like catalyzed by enzymes”.
A prodrug is any compound which is pharmaceutically active in vivo when it undergoes metabolic degradation and the specification does not provide any disclosure of what these compounds might be, that transform in vivo into the instantly claimed compounds. Therefore, the specification does not provide a limiting definition of the term “prodrug”. 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.
Claims 12-15 recite “A method for treating diseases or conditions associated with TRK kinases or NTRK genes”. The inventor or joint inventor should note that claims 12-15 are reach through claim. The claim attempts to obtain protection for subject matter that is prophetic and/or has yet to be invented, including any TRK kinase- or NTRK gene- related disease or condition that has yet to be identified as such. Applicant does not provide any examples of such diseases, and only provides data for the inhibition of tropomysin receptor kinase A (TRKA), TRKB, and TRKC (see Specification, page 79, para 00382, Table 1 IC50 data). The specification does not aid in interpreting the metes and bounds of this limitation, and the scope of the claims is broader than the specification enabling disclosure.
Mechanism is not a practical utility under the US patent practice. To ascertain the practical utilities (diseases), one must read the specification as well as other external sources into the claims, contrary to several precedent decisions by the US courts and official practice. When the specification is read into the claims, the claims would become substantial duplicates. The claims are attempts by applicant to claim treatments of all diseases arising from the mechanism, known today and those that may be discovered in the future. Consequently, the method of treating a TRK kinase- or NTRK gene- related disease or condition has been rendered indefinite by the use of the reach-through protocol.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 13 and 15 recite a broad recitation, and the claims also recite "preferably..." which is the narrower statement of the range/limitation. As an example, claim 13 recites, “the method according to claim 21, wherein the diseases or conditions associated with TRK kinases or NTRK genes are selected from cancer…preferably selected from hepatocellular cancer…”. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Additionally, the use of “preferably” brings into question the exact disease or condition that the applicant is claiming. The phrase “preferably” renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
Written Description
Claims 1-12 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.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus …”) 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 of the instant application embrace compounds of Formula (I), “or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof”. Particularly, the terms “geometric isomer”, “mixture of various isomers”, “prodrug”, and “metabolite” recited in claims 1-12 invoke 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 and knowledge in the art:
The level of skill and knowledge in the art is high.
Partial Structure:
Compounds of Formula (I) have been disclosed and example compound species that would be within the general formula have been disclosed. However, as to the claimed geometric isomer, mixture of various isomers, prodrug, and metabolite, no specific examples are given that would demonstrate possession or put the public in possession of all the claimed geometric isomer, mixture of various isomers, prodrug, and metabolites of Formula (I).
It is generally accepted that geometric isomers and mixtures of various isomers have identical chemical formulae but differ in properties and the arrangement of atoms in the molecule. Additionally, prodrugs and metabolites 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 of Formula (I), and geometric isomers, mixtures of various isomers, prodrugs, and metabolites thereof, are compounds which are allegedly useful in treatment of tropomysin receptor kinase (TRK) related diseases or conditions, for example in the treatment of cancer or inflammation. Although the art recognizes generally accepted definitions, the terms are not explicitly defined by the specification in such a way as to demonstrate that the inventor had possession of the geometric isomers, mixtures of various isomers, prodrugs, and metabolites of Formula (I).
A review of the prior art identifies the reference Kishimoto (Kishimoto, T. et. al. Int. J. Mol. Sci. 2020, 21(1), 34) that discloses a classic case of geometric isomerism. Cisplatin, an active geometric isomer, is active in cancer treatment whereas transplatin, the inactive geometric isomer, is inactive in cancer treatment (Introduction, last sentence). In view of the teachings of Kishimoto, it is unknown which of the geometric isomers 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.
Furthermore, Tague (Tague, A. J., et, al. Med. Chem. Lett. 2021, 12, 413-419) discloses mixtures of isomers of biphenyl antimicrobial peptidomimetic amphiphiles (abstract), and specifically teaches compounds 1-9 (page 416, scheme 5) which are mixtures of positional isomers of aryl ethers of the biphenyls. Compounds 1-9 were tested in antimicrobial assays with varying biological activities. As an example, compound 3 was found to be inactive against C. albicans, whereas compound 9 was found to have a MIC of 1 μg/mL. Further, compounds 1-9 were found to all be inactive against another strain of yeast, C. neoformans var. grubii. Based on the teachings of Tague, it is unknown which mixtures of isomers of Formula (I) claimed by Applicant will be active or inactive, and a skilled artisan would not be able to predict which compounds, of the vast number claimed, will be active or inactive absent evidence.
Additionally, the reference Najjar (Najjar, A. & Karaman, R. Expert Opinion on Drug Discovery, 2018, 14(3), 199-220) discloses successes and failures of prodrugs of known pharmaceuticals, one example of which is also an ester (abstract and page 212, section 3). 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 esters or prodrugs of compounds of Formula (I) claimed by Applicant is 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.
Further review of the prior art identifies the reference Chagas (Chagas, C. M., Moss, S. & Alisaraie, L. Int. J. Pharma. 2018, 549, 133-149) that is drawn to drug metabolites and their adverse reactions (title, abstract). Specifically, Chagas teaches that the metabolites of the fulvestrant, an antineoplastic, are largely inactive and the sole metabolite with activity is 4.5-fold less active than the parent compound (page 144, col 2, para 2). Hence, in light of the teachings of Chagas, it is unknown which of the metabolites of compounds of Formula (I) claimed by Applicant is 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 metabolites would or would not be active.
Since Applicant has not set forth compounds or substituents on Formula (I) in the specification which Applicant considers geometric isomers, mixtures of various isomers, prodrugs, and metabolites, it is not clear what compounds fall under Formula (I). Applicant has not described which geometric isomers, mixtures of various isomers, prodrugs, and metabolites, have the ability to inhibit TRK, and which do not. Stated differently, there is no structure/function correlation and no representative number of specific examples of geometric isomers, mixtures of various isomers, prodrugs, and metabolites that demonstrate which compounds retain activity. Further, one of ordinary skill in the art would not be able to predict the biological activity of the claimed geometric isomers, mixtures of various isomers, prodrugs, and metabolites 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 geometric isomers, mixtures of various isomers, prodrugs, and metabolites, predicting if a certain claimed compound retains the activity and function of the original drug is filled with experimental uncertainty because geometric isomers, mixtures of various isomers, prodrugs, and metabolites contain variation by chemical and physical properties of the molecules.
Method of making the claimed invention:
Although the specification provides a method for making the compounds of Formula(I), no method for making all of the compounds, including the geometric isomers, mixtures of various isomers, prodrugs, and metabolites, 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 geometric isomers, mixtures of various isomers, prodrugs, and metabolites 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 geometric isomers, mixtures of various isomers, prodrugs, and metabolites of Formula (I) because the examples illustrated in the experimental section are limited to only compounds of Formula (I).
Substantial and undue experimentation would be needed to practice Applicant’s invention because the specification lacks sufficient detail to show how to use the geometric isomers, mixtures of various isomers, prodrugs, and metabolites of the instant invention. Further, there is no guarantee that all of the geometric isomers, mixtures of various isomers, prodrugs, and metabolites embraced by the scope of the claims would be use in treatment of TRK-related diseases or disorders, for example in treatment of cancer and autoimmune diseases.
Even with the undue burden of experimentation, there is no guarantee that one would obtain the product of a desired geometric isomers, mixtures of various isomers, prodrugs, and metabolites 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 geometric isomers, mixtures of various isomers, prodrugs, and metabolites 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 generic. It is unquestionable that the claim(s) are broad and generic with respect to all possible compounds encompassed by the claims: the possible structural variations are limitless to any geometric isomers, mixtures of various isomers, prodrugs, and metabolites of the expanded compound species. In the instant case, however, the specification does not disclose a sufficient variety of species to reflect this variance in the genus. Specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims such as, for example, geometric isomers, mixtures of various isomers, prodrugs, and metabolites of the Formula (I).
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. This rejection would be overcome by amending the claims to remove the terms, “geometric isomer”, “mixture of various isomers”, “prodrug”, and “metabolite”.
Scope of Enablement – Compounds
Claims 1-8, 10-11 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 following:
A compound having a structure of formula (I) (as recited in Claim 1)
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or a pharmaceutical composition comprising a compound having a structure represented by Formula (I) (as recited in claim 11) where:
R1 and R2 are as defined in claim 1,
R3, R4, and R6 are H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy only,
X is as defined in claim 1,
n = 1, 2 only,
L is as defined in claim 5,
Ra and Rb are as defined in claim 1,
R5, R5a, R10, and R11 are as defined in claim 7,
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 the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application 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, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention:
The nature of the invention relates to compounds of formula (I) in claim 1. Such compounds are useful as TRK inhibitors. This invention is also directed to compositions comprising said compounds.
Predictability of the art:
The compounds synthesized in the instant specification appear novel. However, the hypothetical compounds in claim 1 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 1. 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.
Level of skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. 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.
The breadth of the claims:
The scope of the claims involves compounds of formula (I), shown below.
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Claim 1 is very broad in the number of variables and the options of substituents for each variable. There is an extremely large amount of hypothetical compounds included in claim 1.
The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary:
The specification provides the synthesis of 48 compounds. Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. For example, there are no working examples of a compound of Formula (I) wherein R3 is a 4-6 membered heteroalicyclic group, or where n = 3, or where R5 is a 7-11 membered bicyclic heteroaryl, as recited in instant claim 1. It would require one skilled in the art, such as a chemist, to perform thousands of reactions to determine which compounds of formula (I) can be prepared and would likely require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Scope of Enablement – Cancer
Claims 12-15 are rejected under 35 U.S.C. 112(a), because the specification, while enabling for:
A method for treatment of specific cancers associated only with specific TRK kinases or NTRK genes but does not provide enablement for general treatment of any or all cancers comprising administering to a subject in need a therapeutically effective amount of:
a compound of Formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof (i.e., as in method claim 12 and corresponding compound/pharmaceutical compositions claims 1-11)
a corresponding pharmaceutical composition thereof (i.e., as in method claim 14), respectively
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:
"Cancer" is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. To be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. "The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors 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. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. 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 environment factors.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
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. Likewise, In re Cortright, 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 applicants' 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."
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
One skilled in the art knows that chemotherapy of brain tumors is especially difficult. This is because 1) the blood-brain barrier, which is often intact in parts or all of a brain tumor, will block out many drugs, as it is the purpose of the blood-brain barrier to protect the brain from alien chemicals, and 2) CNS tumors are characterized by marked heterogeneity, which greatly decreases vulnerability to chemotherapy. As a result, many categories of CNS tumors simply have no chemotherapy available. These include, generally, hemangioblastomas, meningiomas, craniopharyngiomas, acoustic neuromas, pituitary adenomas, optic nerve gliomas, glomus jugulare tumors and chordomas, to name just some. With regard to gliomas, GBM is considered untreatable; no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is radiation and surgery which are used for low grade gliomas (e.g. pilocytic astrocytoma and diffuse astrocytomas), as no drug has been found effective. There is no drug treatment established as effective for optic nerve gliomas or gangliogliomas. Indeed, very few gliomas of any type are treated with pharmaceuticals; it is one of the categories of cancer that is the least responsive to drugs.
Lymphomas of the stomach are not commonly treated with anti-cancer agents per se, but instead, surgery or radiation and antibiotic therapy (e.g. amoxicillin, metronidazole, bismuth, and omeprazole) are the primary treatments.
Neuroendocrine tumors of the cervix generally do not respond to chemotherapy.
A number of sarcomas, including alveolar soft part sarcoma (ASPS), retroperitoneal sarcoma, most liposarcomas, and the assorted chondrosarcomas, are generally considered not to respond to chemotherapy; no chemotherapeutic agent has been established as effective.
It is important to note that tumors can need to be treated quite differently even though they are tumors of the same organ. For example, the drugs used most often to treat Wilms tumor, the most common malignant tumor of the kidneys in children, are actinomycin D and vincristine. Such drugs are never used with clear cell renal carcinoma, which is treated, although without much success, with immunotherapy using the cytokines interleukin-2 and interferon-alpha. However, such immunotherapy has never been established as effective in non-clear cell RCC forms such as papillary renal cell carcinoma. Despite strenuous efforts over a period of decades, no chemotherapeutic agent has ever been found effective against this cancer. Cancers of the stomach can be lymphomas, GISTs, carcinoid tumors, carcinomas, or soft tissue sarcomas, and for a single agent to be effective against all or even most of these categories would be contrary to what is known in oncology.
The scope of treating inflammation generally is extraordinarily broad. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. It is one of the most pervasive of all body processes. Inflammation is a very general term which encompasses a huge variety of specific processes.
The nature of the invention; 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 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.
Amount of guidance provided by applicant; and number of working examples
Applicants provide guidance in the detailed specification and working examples demonstrate the practicality of the claimed invention, which include detailed examples exemplified by working examples of:
synthetic compound examples 1-48 and corresponding intermediates (pages 30-76, para 000154-0350);
isomer compound examples 9 (S-isomer) and 32 (R-Isomer);
experimental in vitro inhibition assay against TRKA/B/C Table 1 (pages 79-80, para 00382)
While the specification provides extensive information directed to above identified compounds, intermediates and synthetic methods of making those compounds, of inhibition activity against TRKA/B/C by claimed compounds and control compound larotrectinib, there are no exemplified examples directed to the use of compounds of the claimed invention for any type of cancer or disease, only that it shows inhibition of TRKA/B/C.
While identified TRK inhibitors of the claimed invention may be useful for cancer diseases or disorders, it cannot be simply willed into existence, because there is:
no reasonably specific guidance is provided in the specification examples to show any in vitro or in vivo biological assays or any preventative protocols directed to any diseases or disorders, directed to cancers, specific or general.
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 cancers, associated TRK 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.
State of the prior art:
The claimed compounds are of Formula (I). So far as the examiner is aware these compounds have not been successfully used as broad range anticancer agents.
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 the described compounds or compositions, which have TRK activity for treating any cancer disease or disorder given that it cannot be achieved:
without undue experimentation as the claimed compounds' use for treating cancer disorders or diseases is not demonstrated and requires extensive further research or testing to determine their effectiveness, because the specification does not teach how to treat cancers as the specification, does not provide sufficient enablement, no data, evidence or teaching to show the claimed method works across the entire breadth of these cancer diseases or conditions, other than to show in vitro inhibitory activity TRKA/B/C; and
there are NO examples and NO prophetic examples identifying specific cancers caused by TRKA/B/C inhibition that are credible to enable a skilled person to practice the invention without undue experimentation to satisfy the enablement requirement.
With regard to cancer treatment methods, given the scope of the many types of cancer included within the claimed invention, their varied etiologies, and the diversity of their patient populations, the disclosure of the specification is insufficient to permit a person skilled in the art to treat the scope of the disorders claimed. Factors such as "sufficient working examples", "the level of skill in the art" and "predictability", etc. have been demonstrated to be sufficiently lacking in the currently examined case for the current method claims. Cancer treatment depends on the different causative agents and cellular mechanisms involved in each type of cancer. Consequently, different treatment protocols are required, depending on the type of cancer.
In view of the breadth of the claims, the pharmacological nature of the invention, the unpredictability of treating cancer, and the lack of working examples regarding the extremely broad therapeutic activity claimed, one skilled in the art would have to perform an undue amount of experimentation to practice the instantly claimed invention commensurate in scope with the claims as currently recited.
Genentech Inc. v. Novo Nordisk NS (CA FC) 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 "[p]atent protection is granted in return for an 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 it is apparent that undue experimentation would be necessary because of variability in prediction of treatment outcome that is not addressed by the present application disclosure, examples, teachings, guidance presented, or from the contents of other art known in the field. Absent factual data to the contrary, the amount and level of experimentation needed is undue.
Therefore, claims 12 and 14 and dependent claims 13 and 15 are rejected under 35 U.S.C. § 112, 1st para. Appropriate action is required accordingly in the instant application.
Scope of Enablement - Prevention
Claims 12 and 14 and dependent claims 13 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph, because the specification, while being enabling for treatment, does not reasonably provide enablement for prevention. 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.
The following Wands factors have been considered if not explicitly discussed: (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.
Of particular note, the specification does not provide any definition of “treatment” or “treating”
so the Merriam-Webster dictionary definition 1, c of “treatment” was employed, which is defined as
“the action or way of treating a patient or a condition medically or surgically: management and care to
prevent, cure, ameliorate, or slow progression of a medical condition.” Therefore, the term “treatment” also embraces the term “prevent”.
It is presumed “prevention” of the claimed condition would require a method of identifying those individuals who will develop the claimed condition before they exhibit symptoms. The current state of the art is that that full scope of diseases claimed within instant claims is not preventable or curable.
The factors to be considered in making an enablement rejection were summarized above. 1) Preventing diseases requires identifying those patients who will acquire the condition before the symptoms occur. This would require extensive and potentially open-ended clinical research on healthy subjects. 2) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical pharmacology and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will develop a disease or condition associated with TRK kinases or NTRK genes before the fact. 6) The artisan using Applicants invention would be a Board Certified physician. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of a disease or condition associated with TRK kinases or NTRK genes. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable for any agent to be able to prevent a disease or condition associated with TRK kinases or NTRK genes. 7) 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). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed conditions.
As claims 13 and 15 depend upon claim 12 and 14, respectively, they are also rejected.
Closest Prior Art
The prior art made of record and not relied upon that is considered closest art to Applicant’s disclosure is found in Chinese Patent CN 114524818 B (published June 23, 2023; effectively filed January 15, 2021).
CN 114524818 B: Present Invention:
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The instant application claims phenyl derivatives in the boxed area, while the reference application claims pyridine derivatives in the boxed area.
Conclusion
No claims allowed.
All claims rejected.
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/L.A.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624