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 1-17 are pending in the current application.
2. This application is a DIV of 17/268,914 02/17/2021 PAT 12139476; 17/268,914 is a 371 of PCT/CN2019/100846 08/15/2019; FOREIGN APPLICATIONS: CHINA 2018109425626 08/17/2018 and CHINA 201910411311X 05/16/2019.
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
3. Claims 1-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The multiple uses of the term "preferably" in claims 1 and 9 is a relative term which renders the claim indefinite. It is improper to speak of preferred embodiments within a claim since this is the purpose of a dependent claim.
Claim Rejections - 35 USC § 112 (a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
4. Claims 1-17 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, does not reasonably provide enablement for prodrugs. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. 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 Z or 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 prodrug is, and on the face there is no clear site for prodrug derivitization like an acid or alcohol.
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 millions of compounds of formula Z an I of claims 34 and 36 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.
5. Claims 1-17 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 inhibiting TRPA1 and treatment of pain it does not reasonably provide enablement for preventing any disease or treating any “disease related to transient receptor channel protein” or inhibiting any other TRP family member. 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).
The specification has some assays for the instantly claimed compounds and pages 93 ff. in HEK293 cells expressing TRPA1, as well as a patch clamp model. The compounds are antagonists of TRPA1. The compounds also perform well in the mouse formalin paw withdrawal test on page 38 ff which is said to be a model of both “acute and inflammatory pain”. In addition the rat hot plate test was performed on pages 40ff, which is a model of acute pain. Two compounds performed well. An acetic acid writhing model was performed was performed with one compound in Example 18. Finally a nerve pain model, rat mechanical allodynia, was also used to test one compound on page 42 ff.
The claims are drawn to preventing and treating all forms of pain. Pain is not a single condition and includes various types: acute pain, inflammatory pain, neuropathic pain, postoperative pain, chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis, neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, various forms of headache such as migraine, acute or chronic tension headache, cluster headaches, maxillary sinus pain, cancer pain, pain of bodily origin, gastrointestinal pain, sport's injury pain, dysmennorrhoea, menstrual pain, meningitis, musculoskeletal pain, low back pain e.g. spinal stenosis, prolapsed disc, sciatica, angina, ankylosing spondyolitis, gout, burns, scar pain, itch and thalamic pain such as post stroke thalamic pain, nerve injury, the "dynias", e.g., vulvodynia, phantom limb pain, root avulsions, Pain disorders include central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (e.g, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia); perioperative pain (general surgery, gynecological), dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno- synovitis and gout), and so on. It is not generally possible to successfully predict the treatment of pain from certain tests in animals, like the writhing test: “Predictiveness-in terms of clinical applicability-is an absolute requirement in nociceptive tests for two reasons. First because it is necessary when searching for new molecules with therapeutic value to avoid false positives and false negatives (Collier, 1964; Chau, 1989). For example, the writhing test, which is very sensitive but only weakly predictive, has to be reserved for initial pharmacodynamic screening so that potentially analgesic substances are not missed (Hendershot and Forsaith, 1959; Loux et al., 1978; Dubinsky et al., 1987).” Le Bars, et. al. “Animal Models of Nociception” Pharmacological Reviews 2001, 53, 597-652, at pg. 634 column 2, paragraph 2. As discussed above there are a number of distinct pain types, and no compound is effective at treating all these distinct types. However MPEP 2164.02 states “[A]n in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing the PTO decision based on finding that in vitro data did not support in vivo applications). Since the initial burden is on the examiner to give reasons for the lack of enablement, the examiner must also give reasons for a conclusion of lack of correlation for an in vitro or in vivo animal model example. A rigorous or an invariable exact correlation is not required, as stated in Cross v. Iizuka, 753 F.2d 1040, 1050, 224 USPQ 739, 747 (Fed. Cir. 1985): [B]ased upon the relevant evidence as a whole, there is a reasonable correlation between the disclosed in vitro utility and an in vivo activity, and therefore a rigorous correlation is not necessary where the disclosure of pharmacological activity is reasonable based upon the probative evidence. (Citations omitted.)”
While there is no “rigorous or an invariable exact correlation” between the assays in the specification, based upon the fact that compounds performed well in the assays it may be possible to treat but not prevent certain types of pain as discussed above. The claims however attempt to treat any “disease related to transient receptor channel protein”. There is no such known set of diseases and attempts to identify the role of these proteins in disease is ongoing. While claims 1 and 15 limit the consideration to TRPA1, claim 9 is drawn to any TRP protein. The Transient Receptor Potential (TRP) channels are a large family of integral membrane proteins that act as cellular sensors. They differ widely in terms of ligand and function, there are currently 9 proposed subfamilies: TRPC involved in various signaling pathways and store-operated calcium entry; TRPV (Vanilloid) which respond to protons, heat and capsaicin; TRPVL; TRPM (Melastatin): Involved in diverse processes, including cold sensation and magnesium homeostasis and cold sensing; TRPA: TRPA: A for "ankyrin", is named for the large amount of ankyrin repeats found near the N-terminus and is primarily found in afferent nociceptive nerve fibers and is associated with the amplification of pain signaling as well as cold pain hypersensitivity; TRPP: P for "polycistin", is named for polycystic kidney disease, which is associated with these channels, TRPML is not highly characterized; TRPS: S for Soromelastatin, was named as it forms a sister group to TRPM. TRPS is broadly present in animals, but notably absent in vertebrates and insects (among others). TRPS has not yet been well described functionally; TRPN: TRPN was originally described in Drosophila melanogaster and Caenorhabditis elegans as nompC, and has been implicated in mechanosensation (including mechanical stimulation of the cuticle and sound detection) and cold nociception a mechanically gated ion channel; TRPML, ML for "mucolipin", gets its name from the neurodevelopmental disorder mucolipidosis IV. TRPML is still not highly characterized. There is an additional family labeled TRPY that is not always included in either of these groups. Genericizing TRPA1 data to all TRP channels makes no sense, given that many of these channels have no ligands and no clear function and have not been studied at all. The ones that have ligands bind to radically different compounds than the ones claimed. For example capsaicin activates TRPV1 while menthol acts upon TRPM8. The only conclusions one can draw from data at TRPA1 is in regard to the functional biochemistry of TRPA1 not other channels. The biochemistry would also have to involve inhibition, while the claims are drawn to “a disease related to TRP” or TRPA1 which would include diseases related to conditions perhaps treatable by additional functions. “TRPA1 is activated by a wide spectrum of covalent, noncovalent, natural, and synthetic compounds. Many TRPA1 antagonists have been identified, and several compounds have been tested in human clinical trials with mixed outcomes. Ten distinct ligand-binding sites have been revealed, spanning intracellular, transmembrane, and extracellular domains.” Cole “Structural pharmacology of TRPA1 channel” Trends in Pharmacological Sciences, August 2026, Vol. 47, No. 8 906. “TRPA1 ligands may converge on a shared gating machinery. Agonists acting at distinct sites— including the covalent pocket, vanilloid-like pocket, and intracellular regulatory regions— ultimately promote channel opening by stabilizing conformational changes that straighten the S4–S5 linker and S5 helix, leading to gate dilation. Conversely, antagonists binding to the pore, L4–5/Cyto, L4–5/TM, or extracellular S1–S2 loop sites inhibit channel activation by restricting these gating movements. More distant sites, such as the ankyrin repeat domain targeted by thiadiazoles, likely modulate the same machinery through long-range allosteric communication.” Nothing is known about the binding site of the claimed compounds. According to Cole, “TRPA1 drug discovery has largely focused on highly selective antagonists. A-967079 was shown to abolish JT010-induced pain and decrease the temperature threshold for cold pain by 7.7°C in human pain models [62,63]. Several antagonists have demonstrated robust target engagement in Phase I clinical studies. For instance, GDC-0334 demonstrated strong inhibition of TRPA1-mediated pain, itch, and flare responses in response to topical AITC [17]. BI 1839100 exhibited favorable pharmacokinetics, safety, and dose-dependent inhibition of AITC induced dermal blood flow [64].” The results are mixed as shown in Table 1. Unraveling additional functional biology related to TRPA1 has not been done in the specification.
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.
6. Claim(s) 1-2, 7-10, 15-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gallagher US 7,037,932 B2. Gallagher teaches at least compound 26 on column 68:
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This is a compound claim 1 where A is a thiophene, X is S, n is 1, 2, or 3 and R3 is H, R1/R2 is H/Me, and the compound is in the form of the oxalate salt. According to column 3 lines 3-4 the compounds of the invention are useful for treating various pains and other dysfunctions.1 “The present compounds and salts may be indicated in the treatment of disorders associated with serotonin and norepinephrine dysfunction in mammals, including depression, OCD, anxiety, memory loss, urinary incontinence, conduct disorders, ADHD, obesity, alcoholism, smoking cessation and pain. The compounds of the present invention are particularly suitable for the treatment of pain.” This is supported by the Formalin Paw Assay on column 86 lines 29 ff, “The analgesic effect of compounds of the invention for the treatment of persistent nociceptive pain was demonstrated using the well-known “formalin test.” The formalin test is a model of persistent nociceptive activation induced by tissue injury which can lead to central sensitization. (Shibata, M., Ohkubo, T., Takahashi, H., and Inoki, R., “Modified formalin test: Characteristic biphasic pain response.” Pain (1989) 38: 347–352; and Tolsen, A., Berge, O. G., Hunskaar, S., Rosland, J. H., and Hole, K., “The formalin test: an evaluation of the method.” Pain (1992) 51:5-17.) The effect of compounds of the invention on formalin-induced paw-licking behavior in the rat was investigated as an index of persistent nociceptive activation.”
Gallagher explains on column 4 lines 45-47 “The compounds of the present invention are indicated in the treatment of persistent pain and references herein to pain are intended to refer to persistent pain.” He makes the distinction between acute pain and persistent pain,
on column 4 lines 9-40,
On the other hand, persistent pain can be defined as pain that persists beyond the usual course of an acute disease or a reasonable time for an injury to heal or that is associated with a chronic pathologic process that causes continuous pain or the pain recurs at intervals for months or years. If pain is still present after a cure should have been achieved, it is considered persistent pain. For the purpose of the present invention, persistent pain can be chronic non-remitting or recurrent. The difference in definition between acute and persistent pain is not merely semantic but has an important clinical relevance. For example, a simple fracture of the wrist usually remains painful for a week to 10 days. If the pain is still present beyond the typical course of treatment, it is likely that the patient is developing reflex sympathetic dystrophy, a persistent pain syndrome that requires immediate effective therapy. Early and effective intervention potentially prevents the undue disability and Suffering, and avoids the potential development of a condition that becomes refractory to therapy.
Acute and chronic pain differ in etiology, mechanisms, pathophysiology, symptomatology, diagnosis, therapy, and physiological responses. In contrast to the transitory nature of acute pain, persistent pain is caused by chronic pathologic processes in Somatic structures or viscera, by prolonged and Sometimes permanent dysfunction of the peripheral or central nervous system, or both. Also, persistent pain can Sometimes be attributed to psychologic mechanisms and/or environmental factors.
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.
7. Claims 1-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gallagher US 7,037,932 AND Bymaster, “Duloxetine (CymbaltaTM), a Dual Inhibitor of Serotonin and Norepinephrine Reuptake” Bioorganic and Medicinal Chemistry Letters 2003, 13, 4477. 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)
Gallagher teaches the compounds of Example 48 on column 78:
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Example 49 and on column 79 and Example 50 and 51 on column 80:
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The compounds were effective neurotransmitter reuptake inhibitors similar to duloxetine on column 86 lines 4-16. Duloxetine is mentioned at column 1 lines 44 ff. The Gallagher compounds were effective analgesics as disclosed on column 86 line 18 to column 87 line 19 and also as discussed on column 5 line 1-2.
Subsequent to the work of Gallagher, Bymaster produced thiophene analogs of the compound of 7 Table 3 page 4478, compounds 21 and 23. Compound 21 is the clinically useful drug duloxetine. Upon going from the phenyl to thiophene analog, i.e. compound 7 to 21 there was a marked improvement in 5-HT uptake inhibition. “Of the heterocyclic alternatives synthesized, the thienyl and furan-2-yl analogues 21–23 demonstrated improved 5-HT uptake inhibition, with the furan analogue (23) having a Ki value of 0.7 nM.” “Compound 21 was then chosen for further study. Two chiral routes to the enantiomers of 21 were developed.6”
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The purified isomer of 21, compound 25, is the clinically approved drug duloxetine.
“Further in vivo evaluation of 25 was also made, thus in microdialysis experiments to determine the increase in synaptic concentration of NE and 5-HT in rat, following administration of 25, at 10 mg/kg po increases in basal levels of NE and 5-HT by 208±31% and 353±62%, respectively, were found. Full microdialysis results will be published elsewhere. In summary 25 inhibits binding to human cell lines expressing NE and 5-HT transporters, inhibits the reuptake of NE and 5-HT in rat synaptosomes of 5-HT and NE and increases NE and 5-HT in rat pre-frontal cortex. Compound 25 has been progressed to the clinic (as duloxetine hydrochloride, CymbaltaTM) and has been shown to be effective in the treatment of depression.3”
Ascertainment of the difference between the prior art and the claims
The compounds of the instant claims differ from those of the prior art by bioisosteric replacement of a phenyl ring with either thiophene or furan. Compared to compounds of Gallagher, Example 50 and 51, the elected species is a thiophene isostere. This is shown in Figure 1.
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Example 49 differs from compound I-11 in claim 6 and 14 in the same manner. Duloxetine differs from the elected species by the replacement of the phenyl ring in naphthalene with a furan as shown in Figure 2.
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Finding of prima facie obviousness
Rational and Motivation
Secondary Considerations
(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 prepare the isosteres of the prior art to produce the instant invention. As discussed above, starting from compound Examples 50 and 51 in Gallagher and replacing the phenyl ring with a thiophene, just as Bymaster did to arrive at duloxetine, one would arrive at the elected species. Thiophene is a 6π-electron aromatic compound and isosteric with benzene, such that the sulfur atom in thiophene is approximately equivalent to an ethylenic group. The replacement of a phenyl with a thiophene is a known modification in this particular research area as shown by Bymaster. The experienced medicinal chemist, who would make applicants' compounds, would be motivated to prepare the thiophene analogs of Gallagher based on the expectation that these analogs would have improved potency just as duloxetine did over compound 7, with an order of magnitude increase in potency.
In a similar manner, furan is frequently used as a bioisostere of a benzene ring in medicinal chemistry since it is also isosteric. In the same manner that Gallagher made the furan isosteres of Bymaster compound 7, the instant claims are drawn to the furan bioisosteres of duloxetine. There is an expectation of the same or similar properties since Bymaster discusses the same properties for the benzofurans as compared to the naphthalenes. For these reasons the claims are obvious over the prior art.
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).
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8. Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-9 of U.S. Patent No. 12,570,643 in view of Aboul-Enein pgs. 158-159: “THE CONTROVERSY: SINGLE ENANTIOMER VS. RACEMIC THERAPY. Although the claims at issue are not identical, they are not patentably distinct from each other because while somewhat narrower the claims of the ‘643 are drawn to a method with the first compound in claim 6 as a single stereoisomer, crystal form, HCl salt. Instant claim 14 has the same isomers. Claim 1 is drawn to any salt of this compound and both stereoisomers R/S. This is a genus of two. Claim 14 has the compound as compound I-1. The specification on column 31 lines 7 ff of the issued parent has the HCl salt listed. According to Aboul-Einen developing a single isomer over a racemate is a design choice. “As you now know, and has been known by the pharmaceutical industry for many years, enantiomers and diastereomers are often readily distinguished in biological systems and frequently exhibit different pharmacokinetic (absorption, distribution, metabolism, and excretion) and pharmacodynamic (pharmacological, therapeutic, and toxicologic) effects, Despite this knowledge, it has been the standard practice to produce chiral drugs as racemates [2]. The opinions in the argument of whether all chiral drugs should be produced as single enantiomers spans the ideological spectrum. Some believe that inactive/toxic enantiomers are simply excess weight and risk and should be considered as '"impurities" and eliminated. Others believe that it is more important to consider morbidity and mortality due to a lack of effective treatments when drugs are held up by the slow manufacturing process of producing enantiomerically pure compounds (3). Among the reasons given for ignoring the presence of distomer in drugs has been the contention that "clean drugs" would be difficult and expensive to manufacture [20]. But over the past decade selective synthesis/enantiomer separation techniques have vastly improved, and the cost of such production has dropped accordingly. Some have gone so far as to suggest that the labels of racemic drugs announce that the contents are composed of 50% therapeutically inactive compounds that may or may not be harmless. Along these same lines, others feel that the development of mixtures of geometric isomers/diastereomers is not justified unless they represent a reasonable fixed dose combination [2]. In these cases, the question of whether the optimal ratio of the isomers is produced by the synthetic process needs to examined. Other factors favoring the use of pure enantiomers include less complex pharmacokinetics, concentration-effect relationships and drug interactions, a decreased body burden of xenobiotic material, and, in some cases, improved pharmacological profile. Reasons to continue the production of chiral drugs as racemates include the cases where enantiomers were found to be identical in pharmacological properties or one enantiomer is known to be inert or possess little biological activity [2]. Cayen [29] expressed several reasons why the pharmaceutical industry may want to continue to produce racemic drugs. In addition to the above reasons, he felt that additive or synergistic effects of the enantiomers, high therapeutic indexes, chiral inversions, and indications for life-threatening disease were all factors that should seriously be considered as justifications for the production of racemic compounds. In general published studies do not unanimously agree that all racemic dugs are more harmful than their single isomer counterparts; many times unforeseen benefits have been realized with the inclusion of the so-called “inactive" isomer [3]. In these cases where both enantiomers exhibit desirable but different properties, development of a fixed combination ratio (not necessarily a “true” racemic mixture of 1:1) should be considered. The development of chiral drugs has opened up a number of issues to be considered by regulatory policies and guidelines: acceptable manufacturing controls of ”impurities"; adequate pharmacological and toxicological assessment by pharmaceutical manufacturers; and proper characterization of metabolism and distribution in the drug development and clinical trial phases [2]. Another question that must be addressed is whether the current compounds manufactured as racemates would be “grandfathered" and not subject to new regulatory guidelines [30]. Regulatory authorities currently require explicit justification for marketing racemic drugs. Special guidelines have been issued for chiral drugs stating that the chemical composition of these drugs must be stated and that the pharmacology/toxicology of each enantiomer be thoroughly explored. The more pragmatic conclusion is to evaluate each new pharmaceutical on its own merit. Clearly, it is vitally important that the decision as to whether to produce single enantiomer drugs or racemic mixtures must be based on clinical evaluation of both enantiomers [2]. If one enantiomer is shown to produce significant toxicity or has little or no activity and large-scale synthesis easily achieved, it is obviously more reasonable to produce the compound as the pure, active enantiomer. The first requirement must be that the chirality of the drug be recognized and the eutomer identified [3 1]. The specifications of the drug substance must include assignment of absolute configuration, an enantioselective analytical method, and a full description of the synthesis. More importantly, the need to justify on chemical, preclinical, and clinical grounds the choice of the form chosen for marketing must be added to the current requirements for drug approval. If the new drug is to be marketed as a single enantiomer only the reasons for the choice and documentation of synthesis (including purity, interbatch variation, etc.) and confirmation of optical stability (synthetic and in vivo) need be added. If a racemic mixture is being considered, the pharmacokinetics of both enantiomers must be determined in Phase I studies including possible metabolic interconversions. Many authors believe that it is unlikely that the use of a single enantiomer would significantly improve efficacy; the most likely value is the reduction of adverse side effects. However, these same authors believe the consumer’s dollar and other health care resources would be better utilized on more general measures to reduce the burden of adverse effects.” As such the instant claims are obvious over the prior patent.
9. Claims 1-17 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-23 of copending Application No. 19/468,344. Although the claims at issue are not identical, they are not patentably distinct from each other because the methods of claim 19-23, vis a vis claim 3 are drawn to only the R isomer, the instant claims are drawn to both. Claim 1 is drawn to both stereoisomers This is a genus of two, R/S. Instant claim 14 has the same R isomers and is practically the same genus. Developing a single isomer over a racemate is a design choice. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
10. Claims 1-17 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-37 of copending Application No. 19/647,173. Although the claims at issue are not identical, they are not patentably distinct from each other because the methods of claim 17 of the copending application are drawn to only the S isomer, the instant claims are drawn to both. Claim 1 is drawn to both stereoisomers This is a genus of two, R/S. Developing a single isomer over a racemate is a design choice. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 The method of “inhibiting a transient receptor potential channel” part (a) is inherently met by the administration of the compounds, since the compounds will perform the function upon administration. The complete identity of the diseases in step (b) “related to a transient potential channel protein” is unclear as discussed above in the 112 (a) rejection, however at least the pain and inflammation of claim 7 and 16 admittedly meet this definition. As explained in Gallagher the persistent pains in claims 8 and 17, inflammatory pain, neurogenic pain, neuralgia, mixed pain, cancer-induced pain, also meet this definition. Since persistent pain can involve the viscera, muscle fibers and headaches these pains are treatable. The antidepressant and anxiolytic effects Gallagher describes for the compounds may also be considered as useful for the treatment of pain, since painful patients are inherently depressed. As disclosed in Fitzcharles “Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome” August 2012 pages 1-45; “2.3.4 Antidepressants with pain modulating effects” “Recommendations: 32. The pain-modulating effects of antidepressant medications should be explained to patients with fibromyalgia in order to dispel the concept of a primarily psychological complaint [Level 5 [249], Grade D]. 33. All categories of antidepressant medications including TCAs, SSRIs and SNRIs may be used for treatment of pain and other symptoms in patients with fibromyalgia [Level 1 [243, 248], Grade A], with choice driven by available evidence for efficacy, physician knowledge, patient characteristics, and attention to side effect profile [Level 5, Consensus].” [Page 25]. Gallagher’s compounds fit the profile of Fitzcharles, as selective serotonin reuptake inhibitor (SSRI) and/or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) which are antidepressants, as discussed on column 1. There is also evidence that depression is a disease of claims 1 and 9. “[O}ur findings support the view that the TRPA1 channel could be a novel therapeutic target for the treatment of anxiety and mood disorders.” [Moura “The blockade of transient receptor potential ankirin 1(TRPA1) signalling mediates antidepressant- and anxiolytic-like actions in mice” British Journal of Pharmacology (2014) 171 4289–4299, page 4297 col. 2]
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