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. Claims 1-30 are pending.
Priority
2. This application is a 371 of PCT/US2021/061863 12/03/2021; PCT/US2021/061863 has PRO 63/121,120 12/03/2020. Applicant’s claim for the benefit of a prior-filed application PRO 63/121,120 is acknowledged, however applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, provisional Application No. of PRO 63/121,120 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The ’120 application presents a genus that is different from that of the instant claims and has different species and no doubly charged naked ammonium cations. The provisional 63/121,120 has only the phenyl compounds with a linker X joining a propyl group:
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The genus of claim 10 has pyridine compounds and a large number of other R2 definitions besides the propyl type groups with A, where A is a saturated ring. Claim 10 has a subgenus with the elected species of Formula II-a, and claim 18 has some species of the instant claim 19, however no naked ammonium ions are present and additional compounds, the furans and spirocycles for example are not present. Accordingly there is no support for the claims as presented in the provisional Application No. of PRO 63/121,120. The claims a are afforded the date of December 3, 2021.
Response to Restriction Election
3. Applicant’s election of group II and the species, UMB18,
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in the reply filed on December 8, 2025 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 10-12, 14, 16-17, 19 read on the elected species. The elected species is a compound where in Formula II, R3a/R3b is H and/or the 2-fluoro-phenethyl group, X is CR1d where R1d is H, R1a is H, R1b is -OMe, R1c is H, R2 is the propan-2-ol-(3-piperazine group where Xb is -N-(C1-C5-alkyl)- where the alkyl is methyl. The elected species in a doubly charged form appears to have a codename in claim 19 as 2019 and each enantiomer also in doubly charged naked cation form as 2022, 2023.1 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 the 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, claims 13, 15, 18, which do not read on the elected species is withdrawn. Claims 1-9, 20-30 are withdrawn as being drawn to a non-elected invention.
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.
4. Claims 10-12, 14, 16-17, 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 8-18 of copending Application No. 17/616,586. Although the claims at issue are not identical, they are not patentably distinct from each other because the elected species appears in claim 18 on page 22 of 48 as compound 2110-a, of Formula II-a. The copending generic claims while somewhat narrower are also the subject of the instant claims where in Formula (II) claim 10 R2 is the propan-2-ol-(3-piperazine/3-piperidine/3-pyrrolidine) group where Xb is CH2, -NH- or -N-(C1-C5-alkyl)-. Oddly the claim 1 in the copending has been amended to exclude the elected species with a proviso, while the dependent claim 18 in the copending includes the compound, creating an issue in that application under 112 ((d)/4th paragraph). Besides the elected species the copending claimed genus embraces the other compounds in claim 19 at least where there is a propyl-2-hydroxy-(3-piperazine/3-piperidine/3-pyrrolidine) group as in compounds 2011, 2013, 2014, 2015, 2019, 2020, 2021, 2022, 2023.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
5. Claim 19 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Compounds 2012 to 2028 are drawn to various charged compounds, that are ammonium ions, sometimes doubly charged. Some of the compounds lack a bond to the amino group and instead have a charge where a bond should be which is a drawing error. Assuming the valence were complete the claims are drawn to non-charged balanced groups as there is no counter anion present the structure is incomplete and erroneous.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
6. Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 19 is drawn to ammonium ions. however claim 10 from which it depends while providing for pharmaceutical salts does not provide for naked ammonium ions and no groups attached to the nitrogen(s) are provided to make them tetravalent groups. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
7. Claim 10-12, 14, 16-17, 19 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 salts, solvates, or hydrates of the claimed compounds, it does not reasonably provide enablement for prodrugs or cocrystals. 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. 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 compound the formula I. Directions concerning how to make the prodrugs 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 other than statements on page 29-31 paragraph [0094] ff., which just suggests what some promoieties might be and how to search for a prodrug.
Even for the most basic type of prodrugs or derivatives, 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). h) The breadth of the claims includes all of the billions of compounds of formula I of claim 1 as well as the presently unknown list of potential 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 or derivative does not constitute instructions to the chemist of how to make such a compound.
Regarding co-crystals, the important factors leading to a conclusion of lack of enablement are the absence of any co-crystals formed, the lack of predictability in the art including an admission presented in the arguments, and the scope of the claims. There are no examples of any cocrystals in the specification. According to Matthew L. Peterson et. al. “Expanding the Scope of Crystal Form Evaluation in Pharmaceutical Science” Journal of Pharmacy & Pharmaceutical Science 2006 (9(3):317-326, “Polymorphs of pharmaceuticals and drug candidates can occur in all types of phases (pure compounds, salts, solvates; for examples see Figure 1), though there is no way to predict the practical extent of polymorphism of any given compound (5). Based on recent reviews and commentaries, many strides have been taken towards better understanding of crystal polymorphism of pharmaceuticals (6,7,8). According to lore and some published examples, the puzzling and unpredictable phenomenon of crystal polymorphism has affected many projects in pharmaceutical research and development over the last few decades.” With regard to multicomponent crystals in particular there is even more unpredictability, Peterson states on page 322,
There remain several limitations to the application of what is currently known to the design of useful materials. As mentioned earlier, it remains intractable to reliably predict crystal structure. Multi-component crystals are well out of reach for prediction due in part to complex energetic landscapes, lack of appropriate charge density models and a large number of degrees of freedom, making computation unfeasible. Moreover, there is only a qualitative understanding of the interplay between intermolecular interactions and materials performance, especially for properties relevant to pharmaceuticals such as solubility, dissolution profile, hygroscopicity and melting point.
According to Miller et. al. “Solvent Systems for Crystallization and Polymorph Selection” Chapter 3 in Solvent Systems and Their Selection in Pharmaceutics and Biopharmaceutics Series Biotechnology: Pharmaceutical Aspects Volume VI Augustijns, Patrick; Brewster, Marcus (Eds.) 2007 crystal formation is an “intricate balance between thermodynamic, kinetic, and molecular recognition.” In this case there is no guidance as to what the co-material is and way to know which pairs will facilitate co-crystal formation or to what extent. Saikia “Variable stoichiometry cocrystals: occurrence and significance” CrystEngComm, 2021, 23, 4583–4606 on page 4583 discusses the problems with understanding the stoichiometry:
The existence of different stoichiometry cocrystals of a particular system facilitates the opportunity to acquire more solid forms of a drug.70,71 However, understanding the factors that govern the formation of different stoichiometries is crucial considering their reproducibility and stability.70,71 Moreover, a large number of systems offer stoichiometry variation depending on the coformer, functional groups, molecular symmetry, starting components' ratio etc. and by definition, each stoichiometry is regarded as a new solid form that exhibits distinct properties. Controlling the stoichiometry of cocrystals is vital considering the purity and efficacy of cocrystals.71,72
One cannot predict the crystal packing structure of cocrystals accurately, nor the stoichiometric ratio. The instant specification does not describe any methods to obtain a co-crystal and only describes on page 28 paragraph [0090] what a cocrystal might be:
The term "cocrystal" refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.
There is no reasonable expectation of producing co-crystals. 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. Thus, undue experimentation will be required to practice Applicants' invention.
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.
8. Claim(s) 10-12, 14, 16-17, is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by a publication and based upon a public use or sale of the invention over the STN-Chemical database registry # RN 1070763-39-1 entry for α-[[2-[[[2-(2-fluorophenyl)ethyl]amino]methyl]-5-methoxyphenoxy]methyl]-4-methyl-1-Piperazineethanol, SR Chemical Library Supplier: ChemBridge Corporation ED Entered STN: 04 Nov 2008. This compound is the elected species and reads on claim 10 where in Formula II, R3a/R3b is H and/or the 2-fluoro-phenethyl group, X is CR1d where R1d is H, R1a is H, R1b is -OMe, R1c is H, R2 is the propan-2-ol-(3-piperazine group where Xb is -N-(C1-C5-alkyl)- where the alkyl is methyl. This compound was entered on November 4, 2008 and is listed as being commercially available by the company ChemBridge. The on sale bar is met since the following documentation shows that this material was subject to an offer for communicated by the internet: Online
“http://www.chembridge.com/ordering/terms/“ January 9, 2013. “Format & Packaging Terms
ChemBridge offers a range of standard vial and plate formats for dry powder or DMSO formatted compounds. In addition to our standard options, ChemBridge can accommodate a client's custom vials, plates, labels/barcodes, and plating (including multi-set and vial/plate sets) and delivery formats. Please contact ChemBridge for information on any costs associated with custom options.”
The elected species and other compounds of the invention are admittedly purchased from Chembridge as disclosed on page 142 paragraph [00290], “Exemplary compounds with anti-viral activity include #96509034, 5612793 and 10253964, which were purchased from Chembridge Corp. Additionally, an analogue of #96509034 was also identified to have increased activity (catalog # 27092311).” #96509034 is the elected species as per the specification on page 143 and page 147.
9. Claim(s) 10-12, 14, 16-17, is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Weston, Stuart et. al.2 “The “SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses.” Proceedings of the National Academy of Sciences of the United States of America, 2020, 117(48), 30687-30698 (with SI) published online November 12, 2020. Weston discloses the elected species on page 30691 at Figure 3 box G.
10. Claim(s) 10-12, 14, 16-17, is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Billich US 5,538,997. Billich discloses 2-hydroxy-4-methoxy-benzylamine at col. 11 line 10. This is a compound of claim 10 where in Formula II, R3a/R3b is H, X is CR1d where R1d is H, R1a is H, R1b is -OMe, R1c is H, R2 is H.
11. Claim(s) 10-12, 14, 16-17, is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by a publication and based upon a public use or sale of the invention over the STN-Chemical database registry # RN 1292541-70-1 entry for 2-[[[2-(2-Fluorophenyl)ethyl]amino]methyl]-5-methoxyphenol, SR Chemical Catalog Supplier: Ryan Scientific, Inc. ED Entered STN: 10 May Nov 2011. This compound reads on claim 10 where in Formula II, R3a/R3b is H and/or the 2-fluoro-phenethyl group, X is CR1d where R1d is H, R1a is H, R1b is -OMe, R1c is H, R2 is H. This compound is listed as being commercially available by the company Ryan Scientific.
12. Claim(s) 10-12, 14, 16-17, 19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by a publication and based upon a public use or sale of the invention over the STN-Chemical database registry # RN 1070689-57-4 entry for 1-(2-methoxyethyl)-N-[[2-(2-propen-1-yloxy)phenyl]methyl]-N-[(tetrahydro-2-furanyl)methyl]-4-Piperidinemethanamine, SR Chemical Library Supplier: ChemBridge Corporation ED Entered STN: 04 Nov 2008. This compound is the first compound in claim 19 and reads on claim 10 where in Formula II, R3a/R3b is the methyl-THF selection 4th, or the piperidine group selection 5th, where R5 is the last selection, R1d is H, R1a is H, R1b is H, R1c is H, R2 is C3 alkenyl (allyl). This compound was entered on November 4, 2008 and is listed as being commercially available by the company ChemBridge. The on sale bar is met since the documentation above in the first 102 rejection shows that this material was subject to an offer for sale.
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.
13. Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weston as applied to claims 10-12, 14, 16-17, above, and further in view of Pandit "Introduction to the pharmaceutical sciences" 2006, Lippincott, Williams and Wilkins: Baltimore, page 19 AND Stahl "Handbook of Pharmaceutical Salts: Properties Selection and Use" Verlag Helvetica Chimica Acta: 2002, pgs. 118-121 220-235, 288-289, 300-301 AND Paulekuhn “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database” Journal of Medicinal Chemistry 2007, 50, 6665–6672. 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:
Weston teaches the free base of the elected species as discussed above. According to Weston, page 30693 col. 1 “We further investigated the breadth of antiviral activity of our lead compound UMB18.” The compound was an antiviral lead compound. The prior art discloses the free base of the elected species but does not prepare the salt forms. Claim 19 is indefinite because the structure of the elected species is drawn as a naked cation, however assuming there were a counterion the claims would be obvious. A pharmaceutical chemist would be apprised of the effect of the anion on the pharmaceutical salt. It is routine for a pharmaceutical chemist to perform a salt form optimization. According to Pandit "Introduction to the pharmaceutical sciences" 2006, Lippincott, Williams and Wilkins: Baltimore, page 19:
Pharmaceutical companies often prefer to develop the salt form of a drug rather than the weak acid or base form for several reasons. Salts are usually easier to crystallize into stable, manufacturable crystals, salts dissolve faster in aqueous solutions, salts are more stable on storage, and salts are easier to handle and manipulate during manufacturing. In particular, salts of amine drugs are preferred over the weak base form. Many amines are volatile and unstable, and have a short shelf life as solids. Stability and shelf life improve dramatically if an amine is converted to the hydrochloride salt, for example. [Emphasis added].
They are expected to be crystalline. The salts of strong acids dissolve faster than the free bases, by acting as its own buffer between the salt and the medium:
The most significant impact that two different salts of the same active moiety can have on the pharmacokinetics are observed during absorption, especially when the absorption step is preceded by the dissolution of the drug molecule. This in-vivo dissolution can easily become the rate-determining step for the absorption, rather than the permeation step itself….In a medium of fixed pH and of sufficient buffer capacity, a drug will have the same solubility, regardless whether present in salt form or as free acid or base. What changes, however, with different salts, is the rate of dissolution and, hence, the rate at which the molecules become available for permeation. The explanation for a changed dissolution rate is the fact that the pH in the diffusion layer surrounding the surface of the dissolving drug salt particles differs from the pH prevailing in the bulk of the dissolution medium. For example, in a given medium, a sodium or potassium salt of a weak acid will always create a higher pH in that layer than the corresponding free acid or a salt formed with a weaker base. Conversely, the pH of the diffusion layer of a hydrochloride, or other strong acid salt of a weak base is always lower than that of the diffusion layer of the corresponding free base. The salt effectively acts as its own buffer to alter the pH of the diffusion layer and increases the apparent solubility and, in turn, the dissolution rate of the parent compound in that layer. [Stahl pages 188-120]
Paulekuhn determined the frequency of occurrence of salt forms in the orange book for 25 years. Table 1 on page 6666 shows that 38.6 percent of all drugs were basic salt forms. It was prima facie obvious to one of ordinary skill in the art at the time the invention was made to make the salts of the prior art amine compound because such salts are preferred over the weak base form, for a variety of reasons including improving the pharmacokinetics during absorption due to faster dissolution and improvements in manufacturing (easier to crystallize, more stable on storage, easier to handle and manipulate).
Conclusion
14. 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.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 The structures in claim 19 are not uniform, with compounds 2001-2012 being drawn in bond-line formula while compounds 2013-2028 have all the understood H atoms drawn out. For the compounds in non-bond-line formula the alkyl amines lack a bond to the charge forming H atoms and instead have a charge where a bond should be. The first group of structures also have a resonance hybrid benzene depiction with a circle in the center while the others do not and simply have alternating double bonds.
2 Stuart Weston, Lauren Baracco, Chloe Keller, Krystal Matthews, Marisa E. McGrath, James Logue, Janie Liang, Julie Dyall, Michael R. Holbrook, Lisa E. Hensley, Peter B. Jahrling, Wenbo Yu, Alexander D. MacKerell, and Matthew B. Frieman.