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 .
DETAILED ACTION
1. This application is a 371 of PCT/CN2022/075712 02/09/2022, FOREIGN APPLICATIONS CHINA 202110184793.7 02/10/2021.
Claims 25-45 are pending.
Response to Restriction Election
2. Applicant’s election of group I and the species, compound 1,
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in the supplemental reply filed on April 17, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). According to applicants’ representative claims 25-40 read on the elected species. The elected species is a compound of claim 1 where X3 is O, X2 is O, m is 2, R2 and R3 in one unit are H, in another unit H and methyl, X1 is O, R1 is F, n is 1, R2’ and R3’ are H, R5 is ethyl, R6 is H, Y1 is C, Y2 is N, and R4 is H. Claims 29-30, 35, do not read on the elected species. As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. The search and examination was continued until prior art was found that anticipated or rendered obvious a non-elected species that falls within the scope of the generic Markush claim reading on the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claim 29-30, 35 which does not read on the elected species are withdrawn.
Claim Objections
3. Claims 25-28, 31-34, 36-38, 40 are objected to because of the following informalities: The claims use a tilde, ~, for various ranges of atoms in a number of groupings, but not all, such as “3~10 membered heterocyclic group” “5~10 membered heteroaryl group” etc. In Asian languages, such as Chinese and Japanese, the tilde is used for ranges. In English the tilde is used to indicate approximation (e.g., ~ 30 minutes). Since this is a convention of accepted English, correction is required. Contrast this to an alternate English spelling as discussed in MPEP 608.01 “Examiners should not object to the specification and/or claims in patent applications merely because applicants are using British English spellings (e.g., colour) rather than American English spellings. It is not necessary to replace the British English spellings with the equivalent American English spellings in the U.S. patent applications. Note that 37 CFR 1.52(b)(1)(ii) only requires the application to be in the English language. There is no additional requirement that the English must be American English.” In this case the tilde is being used in the manner of a foreign language. The appropriate correction would be a dash and 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.
4. Claims 25-28, 31-34, 36-40 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 pharmaceutically acceptable salts, solvates, and polymorphs, it does not reasonably provide enablement for prodrugs, active metabolites, or all isomers. 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.
Prodrugs
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to the following:
(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
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Finding a prodrug is an empirical exercise. Predicting if a certain ester of a claimed alcohol, for example, is in fact a prodrug or derivative that produces the active compound metabolically in man at a therapeutic concentration and at a useful rate, is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. For a compound to be a prodrug, it must meet three tests. It must itself be biologically inactive. It must be metabolized to a second substance in a human at a rate and to an extent to produce that second substance at a physiologically meaningful concentration. Thirdly, that second substance must be clinically effective. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large quantity of experimentation. There is no working example of a prodrug of a prodrug in the specification . Directions concerning how to make the prodrugs are not found in the specification. The sole mention of prodrugs is on page 24 of the specification which suggest how to search for one:
Prodrugs can be prepared by modifying functional groups present in a compound, either by routine manipulation, or in vivo, in such a way that they decompose to the parent compound. Various prodrug forms are well known in the art. Discussions about prodrugs are provided in, see, T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Vol. 14 of the ACS Symposium Series, Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association, Pergamon Press, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, the above documents are incorporated herein by reference.
The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body. Wolff, Manfred E. "Burger's Medicinal Chemistry, 5ed, Part I", John Wiley & Sons, 1995, pages 975-977 summarizes the state of the prodrug art. The table on the left side of page 976 outlines the research program to be undertaken to find a prodrug. The second paragraph in section 10 and the paragraph spanning pages 976-977 indicate the low expectation of success. In that paragraph the difficulties of extrapolating between species are further developed. Since, the prodrug concept is a pharmacokinetic issue, the lack of any standard pharmacokinetic protocol discussed in the last sentence of this paragraph is particularly relevant. Banker, G.S. et al, "Modern Pharmaceutics, 3ed.", Marcel Dekker, New York, 1996, pages 451 and 596 in the first sentence, third paragraph on page 596 states that "extensive development must be undertaken" to find a prodrug. Wolff (Medicinal Chemistry) in the last paragraph on page 975 describes the artisans making Applicants' prodrugs as a collaborative team of synthetic pharmaceutical chemists and metabolism experts. All would have a Ph. D. degree and several years of industrial experience. Rautio et. al. “Prodrugs: design and clinical Applications” Nature Reviews Drug Discovery 2008, 7, 255-270 discusses the difficulties and complexities of prodrug design, “Several important factors should be carefully examined when designing a prodrug structure, including: • Parent drug: which functional groups are amenable to chemical prodrug derivatization? • Promoiety: this should ideally be safe and rapidly excreted from the body. The choice of promoiety should be considered with respect to the disease state, dose and the duration of therapy. • Parent and prodrug: the absorption, distribution, metabolism, excretion (ADME ) and pharmacokinetic properties need to be comprehensively understood. • Degradation by-products: these can affect chemical and physical stability and lead to the formation of new degradation products.” No explanation is provided in the specification as to what the structure of the compounds may be or how to make them.
Even for the most basic type of prodrugs, such as esters, extensive experimentation must be undertaken. Each step is fraught with experimental difficulties, see Beaumont “Design of Ester Prodrugs to Enhance Oral Absorption of Poorly Permeable Compounds: Challenges to the Discovery Scientist” Current Drug Metabolism, 2003, 4, 461-485, “Overall, the barriers confronting the oral delivery of prodrugs are considerable. In addition, to improving membrane permeability of a polar active principle, a prodrug should avoid transporter mediated efflux and be designed to yield the active principle into the systemic circulation. Incomplete membrane permeation, efflux, non-esterase metabolism or biliary elimination will lead to a reduction in the potential oral bioavailability of the active principle. Thus, in order to be successful, a prodrug approach must consider the balance of all these issues.” ( Beaumont pg. 463 first column). Beaumont goes on to review several case studies of both successes and failures, leading to the conclusion “Clearly, prodrug strategies have been successful for a number of important therapeutic agents. However, further investigation suggests that the hurdles to oral delivery of an ester prodrug are not trivial. These include maintaining sufficient aqueous solubility, lipophilicity and chemical stability at the same time as enabling rapid and quantitative release of active principle post absorption. In addition, significant nonesterase metabolism and transporter mediated clearance of the prodrug is not desirable. For these reasons, it appears that achieving high oral bioavailability values with a prodrug approach is extremely difficult and a realistic target for oral bioavailability would be 50%. In addition, designing an ester prodrug that balances all of these issues is a difficult undertaking and a robust screening sequence is required in the Discovery environment. However, due to the difficulty in predicting the human disposition of an ester prodrug, it may be necessary to evaluate several examples in human pharmacokinetic studies. Given the complexities outlined in this review, it is recommended that the prodrug strategy is only considered as a last resort to improve the oral bioavailability of important therapeutic agents.” “Predicting the pharmacokinetics (PK) of prodrugs and their corresponding active drugs is challenging, as there are many variables to consider. Prodrug conversion characteristics in different tissues are generally measured, but integrating these variables to a PK profile is not a common practice.” [Abstract Malmborg “Predicting human exposure of active drug after oral prodrug administration, using a joined in vitro/in silico–in vivo extrapolation and physiologically-based pharmacokinetic modeling approach” Journal of Pharmacological and Toxicological Methods 67 (2013) 203–213.] This process is very labor intensive and fraught with experimental uncertainty as discussed in Malmborg page 204, column 1:
Literature advice on prodrug lead optimization and selection strategies include the use of relevant human biological matrices such as plasma, intestinal and liver microsome preparations to predict conversion rates in vivo using an in vitro–in vivo-extrapolation (IVIVE) approach (Simplicio, Clancy, & Gilmer, 2008). On the other hand, others believe that in vitro assays lack the ability to anticipate the actual conditions in vivo and propose to primarily use preclinical in vivo data in the optimization and selection processes (Hsieh, Hung, & Fang, 2009). However, preclinical in vivo data also has limitations in predicting the human situation. For instance, plasma esterase and gut wall CYP3A activity in man is frequently much lower compared to rats (Berry, Wollenberg, & Zhao, 2006; Cao et al., 2006; Fagerholm, 2007b). In that respect, a combination of relevant in vitro assays in an IVIVE approach with in vivo confirmation studies, as recently proposed by Jana et al. (2010), might be the most promising screening strategy. At the same time, this strategy has the drawback of labor-intensity, as it includes finding an in vitro–in vivo correlation in two preclinical species.
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). The breadth of the claims includes a presently unknown list of potential prodrugs of claim 25. Since the structures of these prodrugs and are uncertain, direction for their preparation must also be unclear. Directions to a team of synthetic pharmaceutical chemists and metabolism experts of how to search for a prodrug does not constitute instructions to the chemist of how to make such a compound.
Active Metabolites
Finding a metabolite is an empirical exercise. Predicting the metabolism of a drug is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. See Bernard Testa “Predicting drug metabolism: Concepts and challenges” Pure and Applied Chemistry 2004, Vol. 76, No. 5, pp. 907-914. Testa developed a model system and had an extremely high rate of failure:
“For the 10 substrates, 130 first-generation metabolites were predicted and/or seen experimentally. Correct predictions represented 30 % of these reactions, apparently false positives 62 %, and false negatives 8 %.”
For a compound to be a metabolite, it must undergo a biochemical transformation, and in order to imagine what this metabolism is, we must know what organism this compound has been introduced in. The nature of the invention is the prediction of metabolite and apparently its subsequent preparation. In addition since they must be pharmaceutically active, since the claim specifies It be active, one would also need to test these materials.
There are no metabolites disclosed or suggested, since the structures of these additional metabolites are not known, direction for their preparation must also be unknown. Directions to a team of synthetic pharmaceutical chemists and metabolism experts of how to search for a metabolite hardly constitute instructions to the chemist of how to make such a compound. The artisans making Applicants' metabolites as a collaborative team of synthetic pharmaceutical chemists and metabolism experts. All would have advanced degrees and years of industrial experience. 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). The breadth of the claims includes an unknown list of potential metabolites of compounds of claim 25.
Isomers
The claims embrace all possible isomers, constitutional, structural, stereoisomers, etc. No synthesis or information is given as to what these compounds are, therefore no synthesis can be undertaken. A key issue that can arise when determining whether the specification is enabling is whether the starting materials or apparatus necessary to make the invention are available. In the biotechnical area, this is often true when the product or process requires a particular strain of microorganism and when the microorganism is available only after extensive screening. The Court in In re Ghiron, 442 F.2d 985, 991, 169 USPQ 723, 727 (CCPA 1971), made clear that if the practice of a method requires a particular apparatus, the application must provide a sufficient disclosure of the apparatus if the apparatus is not readily available. The same can be said if certain chemicals are required to make a compound or practice a chemical process. In re Howarth, 654 F.2d 103, 105, 210 USPQ 689, 691 (CCPA 1981). According to the U.S. Court of Customs and Patent Appeals in In re Argoudelis , De Boer, Eble, and Herr 168 USPQ 99 at 101, "[o]rdinarily no problem in this regard arises since the method of preparing almost all starting materials can be set forth in writing if the materials are not already known and available to the workers in the art, and when this is done the specification is enabling to the public". In re Argoudelis , De Boer, Eble, and Herr 168 USPQ 99 at 104, "it is essential that there be no question that, at the time an application for patent is filed, (emphasis in original) the invention claimed therein is fully capable of being reduced to practice (i.e., that no technological problems, the resolution of which would require more than ordinary skill and reasonable time, remain in order to obtain an operative, useful embodiment)." That is not the situation here. There are no directions to prepare any isomers and the structure is not even disclosed. In re Howarth, 210 USPQ 689, (claimed derivatives of clavulanic acid not enabled by specification lacking information of how prepare the clavulanic acid or directions to reference materials containing such information), Ex parte Schwarze 151 USPQ 426 (where starting material is not known to art as of date of filing application, there must be included a description of preparation thereof to enable one skilled in this art to carry out applicant's invention), Ex parte Moersch 104 USPQ 122 (claims to process for the production of (1)-y1-p-nitrophenyl-2-dichloracetamindo-propane-1,3-diol not enabled because of failure to describe source or method of obtaining starting compound; although starting compound is identified by means of appropriate name and by structural formula). Even if the discussion were limited to isomers of alkyl groups several thousand possible chemical structure exist for this formula. At least for hydrocarbon alcohols the number of possible isomers has been calculated, Henry R. Henze and Charles M. Blair "THE NUMBER OF STRUCTURALLY ISOMERIC ALCOHOLS OF THE METHANOL SERIES" Journal of the American Chemical Society 1931, 3042. For a hydrocarbon alcohol series with 20 carbons (C20), 5,622,109 different isomers exist. The instant claims are more complicated because the claims are not just drawn to alcohols, but also pages of generic groups. The factors outlined in In Re Wands mentioned above apply here, and in particular as per the MPEP 2164.01 (a): “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).” It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation.
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.
5. Claim(s) 25-28, 31-34, 36-40 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brighty US 5,037,834. Claim 39 is drawn to the compound 1, the elected species, and isomer thereof. Compound 1 has a molecular formula of C20H18FN5O3. Brighty US 5,037,834 on col. 19 lines 1-5 teaches Example 14, 7-6-(2-Amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4- oxo-quinoline-3-carboxylic acid which also has a molecular formula of C20H18FN5O3, making it an isomer of claimed compound 1.
Claim Rejections - 35 USC § 103
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.
6. Claim(s) 25-28, 31-34, 36-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cui WO 2019023417 A1 (cited on the IDS) in view of Silverman, R.B. The Organic Chemistry of Drug Design and Drug Action 1992, Academic: New York, pg 19 AND Zhu WO 2019206069 A1 (cited on the IDS, English equivalent is US 12,129,258). The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Cui teaches compounds of the compounds of the instant claims that are removed by a proviso regarding m on page 2 of claim 25. On page 10 a genus is taught which is essentially the genus of Formula I-1 in claim 26:
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R9 in preferred embodiments is CN as shown on page 12:
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The genus is supported by a number of species on pages 14-15.
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Silverman teaches that “Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties.” He goes on to state “Erlenmeyer’s 1948 definition of “classical isosteres” as “atoms, ions, or molecules in which the peripheral layers of electrons can be considered to be identical”. Table 2.2 lists several of these classical isosteres under heading 2 “Bivalent atoms and groups” the ether linkage (-O-) is listed as a classical bioisostere of the amino linker (-NH-).
Ascertainment of the difference between the prior art and the claims
The proviso in claim 1 excludes the compounds of Cui:
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The elected species, compound 1, and other compounds differ only by the bioisosteric replacement of an amido nitrogen with an oxygen. A side by side comparison with the compound Cui and compound 1 is shown below:
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Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to use analogs of those of Cui to produce the instant invention. Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties. Erlenmeyer’s 1948 definition of classical isosteres includes the ether linkage (-O-) as a classical bioisostere of the amino linker (-NH-). The only difference between the elected species and other claimed compounds from those of the patent claims is the bioisosteric replacement of amino, -NH-, with an ether linkage (-O-), i.e, amide to ester. The level of ordinary skill in the art is high, and would be someone with synthetic chemistry experience and biochemistry knowledge. The medicinal chemist would be motivated to prepare these bioisosteres based on the expectation that such bioisosteres would have similar properties and upon the routine nature of such experimentation in the art of medicinal chemistry. According to Silverman, “Bioisosterism is a lead modification approach that has been shown to be useful to attenuate toxicity or to modify the activity of a lead, and it may have significant role in the alteration of metabolism of a lead.” Thus in addition to obtaining a compound with “broadly similar biological properties” improvements in properties could be obtained, thus a finding of obviousness type is appropriate in this case.
Beyond Cui and Silverman, this technique has already been applied to these compounds by Zhu, WO 2019206069 A1. Zhu made compounds like example 1 in the US equivalent, such as Example 1:
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These compounds are bioisosteric replacements of the Cui WO 2018022911 A1 compounds. Since this was already known to give the same or similar results in cannot be considered inventive.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
7. Claim(s) 25-28, 31-34, 36-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cui WO 2019023417 A1 in view of Shah “The role of fluorine in medicinal chemistry” Journal of Enzyme Inhibition and Medicinal Chemistry, October 2007; 22(5): 527–540. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Cui teaches compounds of the compounds of the instant claims that are removed by a proviso regarding m on page 2 of claim 25. On page 10 a genus is taught which is essentially the genus of Formula I-1 in claim 26:
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R9 in preferred embodiments is CN as shown on page 12:
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The genus is supported by a number of species on pages 14-15.
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Shah states, “Fluorine substitution has been extensively investigated in drug research as a means of enhancing biological activity and increasing chemical or metabolic stability.” Page 527.
“Despite the fact that fluorine is slightly larger than hydrogen, several studies have demonstrated that it is a reasonable hydrogen mimic and is expected to cause minimal steric perturbations with respect to the compound’s mode of binding to a receptor or enzyme.” Page 528
“1. Improved metabolic stability
Metabolic stability can determine the bioavailability of compounds and substitution with fluorine at the site of metabolic attack can prevent oxidative metabolism based on the fact that the C–F bond is more resistant to attack than the C–H bond. Also, substitution at adjacent or distal sites to the site of metabolic attack can also affect drug metabolism due to inductive/resonance effects or conformational and electrostatic effects.” Page 528
“One of the challenges faced in drug discovery is that of low metabolic stability. Lipophilic compounds are susceptible to oxidation by liver enzymes, namely cytochrome P450. This can be overcome by increasing the polarity of the compound or alternatively introducing a fluorine atom into the compound to alter the rate, route or extent of drug metabolism. The latter can be achieved by fluorine substitution at the metabolically labile site or at adjacent or distal sites to the site of metabolic attack provided that this does not compromise binding to the target protein.” [Page 528].
“The main rationale for introducing fluorine into compounds is either to improve the metabolic stability, alter the physicochemical properties or improve the binding affinity of these compounds. These strategies are already widely used and established by medicinal chemists in the processes of drug discovery and development. At present, fluorine is often introduced into molecules ad hoc but it can be speculated that it could be involved in a more rational approach to drug design where
various techniques could be used to determine where to substitute fluorine atoms to maximise activity.” [Conclusions page 537]
Ascertaining the differences between the prior art and the claims at issue.
The proviso in claim 1 excludes the compounds of Cui:
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The compounds 13, and other compounds, differ only by the replacement of hydrogen atom with a fluorine. A side by side comparison with the Cui compound and compound 13 is shown below:
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Resolving the level of ordinary skill in the pertinent art, considering the objective evidence. Finding of prima facie obviousness Rationale and Motivation (MPEP 2142-2143)
The differences between the prior art compound is an H to F substitution. The fluorinated analog has a sufficient similarity in size and shape to the non-fluorinated analog to fit the active site of the target protein, so they would be expected to have similar inherent biological activity. One of ordinary skill would be further motivated to make this specific fluorinated analog because he or she would expect the compounds to have a greater biological half-life and improved biological properties. This is the strongest rationale as set forth in the MPEP 2144
“II. THE EXPECTATION OF SOME ADVANTAGE IS THE STRONGEST RATIONALE FOR COMBINING REFERENCES
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.” One of ordinary skill would be motivated to make the compounds of the invention because he would expect the compounds to have similar properties, indeed we see that these compounds have the same property as kinase inhibitor.
8. Claim(s) 25-28, 31-34, 36-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cui WO 2019023417 A1 in view in view of Wislicenus, J. “Adolph Strecker’s Short Textbook of Organic Chemistry” 1881, Spottiswoode: London, pages 38-39. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Cui teaches compounds of the compounds of the instant claims that are removed by a proviso regarding m on page 2 of claim 25. On page 10 a genus is taught which is essentially the genus of Formula I-1 in claim 26:
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R9 in preferred embodiments is CN as shown on page 12:
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The genus is supported by a number of species on pages 14-15.
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Ascertainment of the difference between the prior art and the claims
The proviso in claim 1 excludes the compounds of Cui:
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The compounds 11, and other compounds, differ only by the lengthening of the alkyl chain by methylene groups. A side by side comparison with the Cui compound and compound 11 is shown below:
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Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to use analogs of the prior art to produce the instant invention. Analogs differing only in the length of an alkyl chain are called homologs and are prima facie obvious, and require no secondary teaching. Homologs have long been known to exhibit similar properties as evidenced by page 38 of Wislicenus:
HOMOLOGY AND HOMOLOGOUS SERIES,
48. In opposition to the remarkable differences between organic bodies of like molecular formulae, is the fact that bodies of different molecular composition frequently exhibit great similarity in all their chemical and physical properties. The compounds in which these analogies are most marked are those whose formulae differ by CH2, or a whole multiple thereof, nCH2, and whose molecular weights differ therefore by ± 14n.…This analogy of structure is especially shown in the fact that like reagents produce like changes, and further that the resulting products of such changes agree in properties, but differ in composition by CH2. Such bodies are termed homologous compounds. They form members of a natural family of bodies which can be arranged according to their increasing contents of carbon. The similarity of physical properties between the members of a homologous series is greater the nearer they stand to one another on such a list that is, the less they differ in chemical composition.
Analogs differing only in a single methylene in an alkyl chain, are prima facie obvious, and require no secondary teaching, see In re Coes, Jr. (CCPA 1949) 173 F2d 1012, 81 USPQ 369. In re Shetty, 195 USPQ 753, In re Wilder, 195 USPQ 426, and Ex parte Greshem, 121 USPQ 422 all feature a compound with a two carbon link rejected over a compound with a one carbon link. Similarly In re Chupp, 2 USPQ 2nd 1437 have a one-carbon link unpatentable over a two-carbon link. Ex parte Ruddy, 121 USPQ 427 has a three-carbon link unpatentable over a one-carbon link. Ex parte Nathan, 121 USPQ 347 found the insertion of an ethylene linkage obvious. The variation was per se obvious in all these cases and did not require a specific teaching.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
9. Claim(s) 25-28, 31-34, 36-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhu WO 2019206069 A1(English equivalent is US 12,129,258) in view of Fleming “Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore.” J. Med. Chem. 2010, 53, 7902–7917 AND Cui WO 2019023417 A1. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
Determining the scope and contents of the prior art:
Zhu teaches the des-cyano compounds of the instant claims on column 7 and 8 useful for same purpose as the instant claims, a few examples are shown below:
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1016
664
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Col. 2 defines a genus encompassing those species:
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229
361
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R1 and R2 are defined as -CN as the last selection.
These would be claimed compounds where instant -CN is H.
According to Fleming page 7902 col. 1, “Over 30 nitrile-containing pharmaceuticals are prescribed for a diverse variety of medicinal indications with more than 20 additional nitrile-containing leads in clinical development. Trends identifying the roles of the nitrile in medical agents have emerged as the number of nitrile-containing pharmaceuticals has increased.” Fleming on page 7909 col 2 last paragraph discusses the choice of nitrile as a preferred substituent in drugs, “7. The nitrile group improvesADME178-toxicology profiles. Computational properties and empirical rules such as Lipinski’s rules179 are routinely employed to guide structure-based drug design. While a potent molecule is essential for drug discovery, ultimately ADME-Tox properties decide which molecule is advanced into clinical trials. During optimization, leads tend to increase in size and lipophilicity180 which can be offset by introducing the sterically insignificant nitrile group. Replacing a hydrogen with a nitrile can roughly lower cLogP181 by half an order of magnitude and nearly an order of magnitude reduction for logD.182 A more dramatic decrease in lipophilicity by over a full order of magnitude for cLogP/logD often occurs when replacing a halogen or methyl group by a nitrile.”
Ascertaining the differences between the prior art and the claims at issue.
The compounds of Zhu above have an H atom on the phenyl ring, while the claimed compounds have a nitrile (-CN) in this position.
Finding of prima facie obviousness
Rational and Motivation
(MPEP 2142-2143)
It was prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to prepare cyano analogs of those of the Zhu compounds to produce the claimed compounds because of the expectation that the compounds would have similar properties and even improved properties. This substituent was explicitly listed as an option for R1 and R2 by Zhu in the generic description. The replacement of H with CN, was known at the time the invention was made to lead to improved properties in drug compounds as shown by Fleming. The CN analogs have sufficient similarity in size and shape to the non-cyano analogs to fit the active site of the target protein, so they would be expected to have similar inherent biological activity and improved half-life based upon reduced metabolism and increased lipophilicity which would improve bioavailability. This is the strongest rationale as set forth in the MPEP 2144, “II. THE EXPECTATION OF SOME ADVANTAGE IS THE STRONGEST RATIONALE FOR COMBINING REFERENCES
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.”
Beyond Zhu and Fleming, this technique has already been applied to these compounds by Cui. Cui made the exact modifications to his previous series of compounds as discussed above in the 103 rejection over Cui. These compounds are the -CN analogs of the Cui WO 2018022911 A1 compounds. Since this was already known to give the same or similar results it cannot be considered inventive.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
10. Claims 25-28, 31-34, 36-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12,129,2581 in view of Fleming “Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore.” J. Med. Chem. 2010, 53, 7902–7917 AND Cui WO 2019023417 A1. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims are drawn to the des-CN compounds discussed in the 103 rejection above and are obviousness type double patenting for the same reasons as given in the 103 rejection over the same.
Conclusion
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 The instant inventors Yang, Yanqing; Hu, Wei and Wu, Wei are listed on the ‘258 patent.
Prosecution Insights