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/CN2022/093265 05/17/2022: FOREIGN APPLICATIONS CHINA 202110555984.X 05/20/2021.
Claims 1-13 are pending.
Response to Restriction Election
2. Applicant’s election of group I and the species, compound 1
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in claim 9, in the reply filed on April 2, 2026 is acknowledged. The election was made without traverse. According to applicants’ representative claims 9-10 read on the elected species. Claim 10 does not read on the elected species and depends upon claim 1, which does not read on the elected species. As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. 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is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claims 1-8, 10 which do not read on the elected species are withdrawn. Claims 11-13 drawn to a non-elected invention are also withdrawn.
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.
3. Claim 9 is 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 salts, esters, stereoisomers, tautomers, polymorphs, solvates and isotopically labeled compounds, metabolic product of deacylation vitamin B1 and phosphate metabolites, it does not reasonably provide enablement for prodrugs or additional metabolites. 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. Finally the compounds are already prodrugs. Is this a prodrug of a prodrug? There is no working example of a prodrug of a prodrug in the specification . Directions concerning how to make the prodrugs of the prodrug are not found in the specification. 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 prodrugs. 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 of compounds that are already prodrugs does not constitute instructions to the chemist of how to make such a compound.
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 one would also need to test these materials. With that being said, the compounds are known generally as S-Acyl derivatives of vitamin B1 and some metabolism is expected. Once in the blood and liver, thioesterases hydrolyze the S-acyl group off the molecule, converting it into thiamine. The canonical compound in this class is benfotiamine. “A few years, later Shindo and coworkers [32–35] studied in more detail the mechanism of absorption and the metabolic fate of benfotiamine in animal tissues. Their results suggested that benfotiamine (given orally) is first dephosphorylated to S-benzoylthiamine by the ecto-alkaline phosphatase present in the brush borders of intestinal mucosal cells. The more lipophilic S-benzoylthiamine then diffuses through the membranes of intestinal and endothelial cells and appears in the venous mesenteric blood. A significant part of S-benzoylthiamine is captured by erythrocytes [34] and converted to free thiamine through a slow non-enzymatic transfer of the S-benzoyl group to SH groups of glutathione. In the liver, the remainder can be enzymatically hydrolyzed to thiamine and benzoic acid by thioesterases present in the hepatocytes.” [Volvert “Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives” BMC Pharmacology 2008, 8:10, 1-11]
Beyond these metabolites there are no expected additional 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 a 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 all of the presently metabolites of compounds of claim 9.
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.
3. Claim(s) 9 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hirano JP 40012514 (machine translation and STN abstract attached). Compound 9 in claim 9 is taught in Example 5, “ S-furoyl derivative of thiamine B1 monophosphate”. “These compounds all possess vitamin activity; they are not degraded by vitamin B1-degrading enzymes and are absorbed extremely effectively from the gastrointestinal tract upon oral administration, making them useful as pharmaceutical agents.”
4. Claim(s) 9 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bak “Vitamin B1 Thiamine” A Publication of Warde Medical Laboratory 2008 Volume 19, Number 1, 1-8. As Ward explains “Vitamin B1 (Thiamine) is a water-soluble vitamin of the B group. In animal tissues, it is present mainly in phosphorylated form, with thiamine pyrophosphate being the most abundant. The pyrophosphate form is a coenzyme of five different enzymes involved in carbohydrate and lipid metabolism. Vitamin B1 is absorbed by the small intestine by a specific, easily saturable mechanism, which can be impaired by alcohol, and by synthetic or natural thiamine antagonists present in food.” As discussed above all of the claimed compounds are S-acyl thiamine compounds. Once in the blood and liver, thioesterases hydrolyze the S-benzoyl group off the molecule, converting it into free, water-soluble thiamine. Since the claims are drawn to metabolites, they are drawn to vitamin B1 thiamine. Besides thiamine the various phosphorylated forms discussed in Bak are also metabolites as shown by Volvert discussed above and anticipate the claims.
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.
5. Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhong WO 2020108478 A1 (cited on the IDS, English equivalent is US 20220089621) 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)
On page 2 of Zhong US ‘621 the following genus is disclosed:
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The elected species is the compound where one of R1 and R2 and R3 is H, the others are n-propyl. A number of nearly identical specific compounds are also disclosed, including compound 1-13 on page 11 ff.:
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Compound 1-14:
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Compound 1-15
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Compound 1-13 is isomeric, with the same alkyl formula on the S-acyl group. The second compound in claim 9, compound 2 is isomeric to compound 1-15. Compounds 1-14 is a homolog differing in only 1 methylene group to the elected species.
Ascertainment of the difference between the prior art and the claims
The prior art differs only in the identity of the alkyl group which is listed generically as propyl. Between the compounds of claim 9
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Compound 1-13 is isomeric to the elected species, with the same alkyl formula on the S-acyl group. The second compound in claim 9, compound 2 is isomeric to compound 1-15. Compounds 1-14 is a homolog differing in only 1 methylene group to the elected species.
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 the prior art to produce the instant invention. Analogs differing only in the length of an alkyl chain , 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.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
6. Claim 9 is rejected under 35 U.S.C. 101 because the claimed invention is directed to product of nature judicial exception without significantly more. The claim(s) recite(s) metabolites, which includes vitamin B1, thiamine and its various phosphorylated forms as discussed above. Once in the blood and liver, thioesterases hydrolyze the S-acyl group off the molecule, converting it into thiamine1. As explained by Warde, “All plant and animal tissues contain vitamin B1, and so the vitamin is present in all natural unprocessed foods. Rich sources of vitamin B1 include yeast, pork, legumes, beef, whole grains, oatmeal, and nuts.” This judicial exception is not integrated into a practical application because it is just a molecule found in nature. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims are drawn to vitamin B1, thiamine, and its various phosphorylated forms which are all products of nature.
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.
7. Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8, 10-11 of U.S. Patent No. 11,591,3542. Although the claims at issue are not identical, they are not patentably distinct from each other because the first two compounds in claim 9 are alkyl compounds embraced by the ‘354 patent. The elected species with 2-propyl pentane is the compound where in claim 4, where one of R1 and R2 and R3 is H, the others are n-propyl. The second compound in claim 9 is similar with ethyl as the choice.
Conclusion
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 Phosphorylations also occur as discussed in Volvert.
2 The issued patent US ‘354 and the instant application have the common inventor ZHANG, Huan.
Prosecution Insights