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 .
Status of Claims
Claims 1-19 are pending.
Claims 1-19 are rejected.
Claims 20-33 are canceled.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) is acknowledged. The instant application claims priority to U.S. Provisional Application No. 63/389,763, filed July 15, 2022. The instant application, filed July 17, 2023, is entitled to the claim for domestic benefit because July 15, 2023 fell on a Saturday. See 35 U.S.C. 119(e)(3).
Information Disclosure Statement
The Information Disclosure Statement (“IDS”) submitted on Jan. 19, 2024 was filed is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Specification
A substitute specification including the claims is required pursuant to 37 CFR 1.125(a) because of the blurry chemical structures provided in the specification, e.g., in paragraphs [0006], [0036], [0160]-[00162], and claim 1.
A substitute specification must not contain new matter. The substitute specification must be submitted with markings showing all the changes relative to the immediate prior version of the specification of record. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. An accompanying clean version (without markings) and a statement that the substitute specification contains no new matter must also be supplied. Numbering the paragraphs of the specification of record is not considered a change that must be shown.
Claim Objections
Claim 1 is objected to because the chemical structure provided for Formula (I) is blurry. In particular, the substituent labeled R6 at the 3-position of the piperidine ring appears similar to R5. Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
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.
Claims 10, 12 and 15 are 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.
Claims 10, 12:
According to claim 1, a compound of Formula (I) does not allow for "Z" stereochemistry.
Claim 15:
Claim 1, from which claim 15 depends, requires that the composition comprise "at least one pharmaceutically acceptable excipient," and claim 15 does not require at least one pharmaceutically acceptable excipient.
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 8-12, and 15-18 are obvious over EP ‘508 in view of Brown 2012 and WO ’949:
Claims 1-6, 8-12, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Fay et al., European Patent Specification EP 2076508 B1, published on May 1, 2011 (hereinafter “EP ’508”), in view of Nathan Brown, Bioisosterism in Medicinal Chemistry, in Bioisosteres in Medicinal Chemistry 1, 1-14 (Nathan Brown ed., 1st ed. 2012) (hereinafter “Brown 2012”) and Meyers et al., International Application Publication No. WO 2009/127949 A1, published on October 22, 2009 (hereinafter “WO ’949”).
Claim 1 of the instant application is directed to compositions comprising a benzylidine piperidine substituted urea compound of Formula (I), and encompasses one disclosed compound, for example, Compound A:
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(named 3-hydroxy-N-(pyridazin-3-yl)-4-(3-((5-trifluoromethyl)pyridine-2-yl)oxy) benzylidene)piperidine-1-carboxamide in paragraph [0047] of the Specification).1
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EP ’508 teaches similar benzylidine piperidine substituted urea compounds, which differ primarily by the lack of substitution at the 3-position of the piperidine ring (i.e., the substituent labeled R6 in the instant application). For example, EP ’508 at claim 3 teaches:
EP ’508 at claim 3.
EP ’508 further teaches, and at claim 6, directly claims the compound N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide (hereinafter the “Example 5 compound of EP ’508”). The chemical structure of this compound is provided below. Its synthesis is described in Example 5a and Example 5b of EP ’508 at page 26, lines 17-50, and its observed fatty acid amide hydrolase (“FAAH”) enzyme inhibition kinetics are provided in EP ’508 at page 82, Table 2, Ex. 5 (hFAAH kinact/Ki = 24700 M-1s-1). The Example 5 compound of EP ’508 is analogous to Compound A of the instant application, with the only change being that the 3-position of the piperidine ring lacks hydroxyl substitution (i.e., the substituent labeled R6 in claim 1 of the instant application is H).
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The Example 5 compound of EP ’508 corresponds to the instant compound of Formula (I), wherein R1 is hydrogen, R2 is a 6-membered aromatic heterocycle containing 2 nitrogen ring heteroatoms (pyridazinyl), R3 is hydrogen, R4 is hydrogen, R5 is haloalkyl (trifluoromethyl), R6 is hydrogen, m is 0, n is 0, p is 1, Z1 is N, and Z2 is CH. It may be used in a pharmaceutical composition, as itself or as a pharmaceutically acceptable salt or solvate thereof, and in combination with an excipient. For example, EP ’508 teaches:
The compounds herein, and the pharmaceutically acceptable salts thereof, can be administered as crystalline or amorphous forms, hydrates, solvates, complexes, and tautomers thereof, as well as all isotopically-labeled compounds thereof. They may be administered alone or in combination with one another or with one or more pharmacologically active compounds which are different than the compounds described or specifically named herein, and the pharmaceutically acceptable salts thereof. Generally, one or more these compounds are administered as a pharmaceutical composition (a formulation) in association with one or more pharmaceutically acceptable excipients.
EP’508 at [0070].
While the Example 5 compound of EP ‘508 is identical to the exemplified embodiment of the instant claims (see Compound A above) except for the substitution of a hydroxyl group at the 3-position of the piperidine ring for one of the two hydrogen atoms, one of ordinary skill in the art would have a reasonable expectation of success in substituting a hydroxyl group (i.e., -OH) for a hydrogen at the 3-position of the piperidine ring because: 1) both groups are considered bioequivalent/bioisosteres in medicinal chemistry; and 2) the 3-position of the piperidine ring on this molecular scaffold is amendable to chemical modification for tuning activity. For example, see Brown 2012 and WO ’949.
Brown 2012 teaches a definition of bioisosteres and identifies certain bioisosteres for H:
‘Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physiochemical properties….’
Brown 2012 at 8,
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Brown 2012 at 7.
Brown 2012 further teaches the general acceptance of bioisosterism in the art of medicinal chemistry. For example, Brown 2012 explains that it is routine to identify substituents that are bioisosteric replacements:
When considering a medicinal chemistry project where a lead molecule has been identified, and also chemical handles, to permit the synthesis of many analogues, the project team will identify substituents that are potential bioisosteric replacements using a number of different methods.
Brown 2012 at 9, and
Bioisosteric replacement is often considered when the aims are to maintain enzyme potency while optimizing additional properties, such as cellular penetration, solubility, metabolism, toxicity, and so on.
Brown 2012 at 12.
WO ’949 teaches that the 3-position of the piperidine ring of the Example 5 compound of EP ’508 is amendable to chemical modification for tuning activity. For example, the synthesis of the R6 = CH3 analog of the Example 5 compound of EP ’508, (4E)-3-methyl-N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide, is taught in WO ’949 at page 32, under Examples 1 and 2. The structure of this compound, hereinafter the “WO ’949 methyl analog”, is provided below. WO ’949 teaches that this compound also inhibits the human FAAH enzyme, specifically, with inhibition kinetics of hFAAH Kinact/Ki = 4590, 3120, 683, 495, 254 M-1s-1. WO ’949 at 43-45.2
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A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990). See also MPEP § 2144.09.
One having ordinary skill in the art at the time of the claimed invention would have found it obvious to substitute a hydroxyl group (i.e., -OH) for the hydrogen at the 3-position of the piperidine ring of the Example 5 compound of EP ’508, because Brown 2012 discloses that OH is a classical bioisostere for H. The skilled artisan would have been motivated to select the 3-position of the piperidine ring of the Example 5 compound of EP ’508 for substitution because WO ’949 taught that methyl substitution at that position resulted in a compound that inhibited the human FAAH enzyme. Being a bioisosteric equivalent of the Example 5 compound of EP ’508, it would be obvious to use the hydroxyl substituted compound for the same purposes, namely in a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof, with at least one pharmaceutically acceptable excipient, as taught by EP ’508. There would have been a reasonable expectation of success, because Brown 2012 discloses that bioisosteres are groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physiochemical properties.
While secondary considerations, such as unexpected results in the human FAAH enzyme inhibition kinetics determined for various embodiments of the claimed invention, may provide indicia of unobviousness, the Specification at Table 2, pages 38-39, reports IC50 values for various compounds of Formula (I) within the expected range based upon similar benzylidine piperidine compounds. For example, WO ’949 teaches that methyl substitution at 3-position of the piperidine ring of the Example 5 compound of EP ’508 decreases the human FAAH enzyme inhibition kinetics of the resulting compound, as determined by comparing the reported hFAAH Kinact/Ki values.3 One having ordinary skill in the art at the time of the claimed invention would expect a similar effect caused by hydroxyl substitution at the same position, because Brown 2012 teaches that CH3 and OH are bioisosteric equivalents for H. See supra Table 1.3 from Brown 2012 at 8. According to the Specification of the instant application, hydroxyl substitution at the at 3-position of the piperidine ring of the Example 5 compound of EP ’508 resulted in the expected decrease in the inhibition potency. See Table 2 of the Specification of the instant application, pages 38-39 (confirming that Human FAAH IC50 values reported for hydroxyl substitution (Compounds A-SE, A-RZ, A-RE, A-SZ) are higher than those for the Example 5 compound of EP ’508 (referred to in the Specification as Compound of Formula (II)).
Thus, the invention of claim 1 as a whole is prima facie obvious over the references, especially in absence of evidence to the contrary.
Claims 2-6 and 8-9 read on Compound A and were prima facie obvious at the time of filing for the reasons presented in claim 1.
Claim 10 is directed to the pharmaceutical composition according to claim 1, wherein the compound of Formula (I) is one of the four possible enantiomer/stereoisomers of the exemplified embodiment of the instant claims, Compound A, viz. the (R,E), (S,E), (R,Z), and (S,Z) stereoisomers of Compound A, or a pharmaceutically acceptable salt or solvate thereof.
Claim 11 is directed to the pharmaceutical composition according to claim 1, wherein the compound of Formula (I) is the (R,E) stereoisomer of Compound A, , or a pharmaceutically acceptable salt or solvate thereof.
Claim 12 is directed to the pharmaceutical composition according to claim 1, wherein the compound of Formula (I) is the (R,Z) stereoisomer of Compound A, , or a pharmaceutically acceptable salt or solvate thereof.
While the core structure of Compound A was prima facie obvious at the time of filing for the reasons presented in claim 1, one of ordinary skill in the art would have been motivated to prepare the four possible stereoisomers of the exemplified embodiment of Compound A because the different stereoisomers of the similar WO ’949 methyl analog were known.
WO ’949 teaches that the synthesis of the WO ’949 methyl analog resulted in both of its E and Z isomers, from which the two enantiomers of the E-olefin were isolated.
The reaction was concentrated to give the crude product as a racemic mixture of olefin isomers (-6:1 E:Z). The isomers were separated by chiral SFC on a Chiralpak AS-H column (15% isopropanol/C02) to give the two enantiomers of the E-olefin.
WO ’949 at 32.
A person having ordinary skill in the art at the time of filing would have had a reasonable expectation of success in selecting one of the four possible stereoisomers of the exemplified embodiment Compound A because WO ’949 taught that for the WO ’949 methyl analog, the resulting human FAAH inhibition kinetics were sensitive to the orientation of the methyl group at the 3-position of the piperidine ring.
For example, WO ’949 teaches that for the WO ’949 methyl analog, the human FAAH enzyme inhibition kinetics were dependent upon the chirality of the carbon pertaining to where the methyl substitution occurred. See WO ’949, page 43, Table entries for Ex. 1 and Ex. 2.4
While WO ’949 does not directly teach the human FAAH enzyme inhibition kinetics of the Z stereoisomers of the WO ’949 methyl analog, a person having ordinary skill in the art of medicinal chemistry at the time of filing would have been motivated to investigate the effect of the E/Z orientation of the benzylidine piperidine double bond on the human FAAH enzyme inhibition kinetics of a compound employing the same benzylidine piperidine molecular scaffold because the resulting human FAAH enzyme inhibition kinetics for the WO ’949 methyl analog were sensitive enough to impart an approximately 18-fold less potent hFAAH inhibitor based solely on chirality of the E isomer. Compare the hFAAH Kinact/Ki for Ex. 1 and Ex. 2 reported in the table on page 43 of WO ’949 (4590 and 254 M-1s-1, respectively).
Therefore, one of ordinary skill in the art would have found claims 10-12 prima facie obvious at the time of filing.
Claim 15 is directed to the pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
To the extent that claim 15 limits the bounds of claim 1 to only a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, thereby removing solvates of a compound of Formula (I), while at the same time, expands the bounds of claim 1 by removing the requirement for at least one pharmaceutically acceptable excipient, claim 15 was prima facie obvious at the time of filing for the reasons presented in claim 1. As explained in claim 1, a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, was prima facie obvious at the time of filing.
Therefore, claim 15 was prima facie obvious at the time of filing.
Claim 16 is directed to the pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a solid oral dosage form.
Claim 17 is directed to the pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a tablet.
While EP ’508 does not specifically teach a solid oral dosage form or a tablet form of the pharmaceutical composition of claim 1, one of ordinary skill in the art would have a reasonable expectation of success in developing the pharmaceutical composition of claim 1 in a solid oral dosage form or in tablet form because EP ’508 teaches that the compounds used in the pharmaceutical compositions of EP ’508 may be used in a solid oral dosage form, one of which is in the form of tablets. For example, EP ’508 teaches:
Formulations suitable for oral administration include-solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges which may be liquid-filled; chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal or mucoadhesive patches.
EP ’508 at 12, paragraph [0072], and
“Pharmaceutical composition" refers to the combination of one or more drug substances and one or more excipients. "Drug product," "pharmaceutical dosage form," "dosage form," "final dosage form" and the like, refer to a pharmaceutical composition that is administered to a subject in need of treatment and generally may be in the form of tablets, capsules, liquid solutions or suspensions, patches, films, and the like.
EP ’508 at page 5, lines 44-48.
Since Compound A, i.e., an exemplified embodiment of a compound encompassed by claim 1, is a bioisosteric equivalent of the Example 5 compound of EP ’508, it would be obvious to use it for the same purposes as taught by EP ’508, namely in a pharmaceutical composition, wherein the pharmaceutical composition is a solid oral dosage form or a tablet.
Therefore, claims 16 and 17 were prima facie obvious at the time of filing.
Claim 18 is directed to a method of inhibiting FAAH in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 1.
While EP ’508 does not specifically teach a method of inhibiting FAAH in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 1, one of ordinary skill in the art would have a reasonable expectation of success in developing such a method because EP ’508 teaches that the compounds of its disclosure are effective for such a purpose. For example,
The present invention relates to compounds of Formula I, Formula II and Formula III, compounds specifically named below, and their pharmaceutically acceptable salts, which are effective for inhibiting the activity of FAAH.
EP ’508 at page 6, paragraph [0032], and
The invention also discloses in part, methods of treating FAAH-mediated diseases or conditions including acute pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain urinary incontinence, overactive bladder, emesis, cognitive disorders, anxiety, depression, sleeping disorders, eating disorders, movement disorders, glaucoma, psoriasis, multiple sclerosis, cerebrovascular disorders, brain injury, gastrointestinal disorders, hypertension, or cardiovascular disease in a subject by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds herein, and the pharmaceutically acceptable salts thereof,.
EP ’508 at page 3, paragraph [0009].
Since Compound A, i.e., an exemplified embodiment of a compound encompassed by claim 1, is a bioisosteric equivalent of the Example 5 compound of EP ’508, it would be obvious to use it for the same purposes as taught by EP ’508, namely in a method of inhibiting FAAH in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 1.
Therefore, claim 18 was prima facie obvious at the time of filing.
Claim 19 is obvious over EP ‘508 in view of Brown 2012, WO ’949, Johnson 2011, Mayo 2020 and Doenni 2016:
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over EP ’508 in view of Brown 2012, WO ’949, Johnson et al., “Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor,” ACS Medicinal Chemistry Letters, vol. 2, no. 2, pages 91-96 (2011) (hereinafter “Johnson 2011”), Mayo et al., “Elevated Anandamide, Enhanced Recall of Fear Extinction, and Attenuated Stress Responses Following Inhibition of Fatty Acid Amide Hydrolase: A Randomized, Controlled Experimental Medicine Trial,” Biological Psychiatry, vol. 87, no. 6, pages 538-547 (2020) (hereinafter “Mayo 2020”), and Doenni et al., “Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling,” Brain, Behavior, and Immunity, vol. 58, pages 237-247 (2016) (hereinafter “Doenni 2016).
Claim 19 is directed to a method of treating an autism spectrum disorder or post-traumatic stress disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to any one of claim 1.
EP ’508, Brown 2012, and WO ’949 are relied upon as above.
While EP ’508, Brown 2012, and WO ’949 do not teach a method of treating an autism spectrum disorder or post-traumatic stress disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to any one of claim 1, one of ordinary skill in the art would have a reasonable expectation of success in using such a composition in a method for treating post-traumatic stress disorder in a subject in need thereof, because the Example 5 compound of EP ’508 was used in such a manner. For example, see Johnson 2011 and Mayo 2020.
As background, Johnson 2011 teaches that PF-04457845 is the name assigned to the Example 5 compound of EP ’508.
Herein, we report the discovery and characterization of a highly efficacious and selective FAAH inhibitor PF-04457845 (23).
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Johnson 2011 at Abstract.
Mayo 2020 teaches that PF-04457845 was used as an FAAH inhibitor to assess evidence that human FAAH inhibition may provide a means for the treatment of posttraumatic stress disorder. For example, Mayo 2020 teaches:
METHODS: In this double-blind, placebo-controlled experimental medicine study, healthy adults were randomized to an FAAH inhibitor (PF-04457845, 4 mg orally, once daily; n = 16) or placebo (n = 29) for 10 days. On days 9 and 10, participants completed a task battery assessing psychophysiological indices of fear learning, stress reactivity, and stress-induced affective responses.
Mayo 2020 at Abstract, and
CONCLUSIONS: Our data provide preliminary human evidence that FAAH inhibition can improve the recall of fear extinction memories and attenuate the anxiogenic effects of stress, in a direct translation of rodent findings. The beneficial effects of FAAH inhibition on fear extinction, as well as stress- and affect-related behaviors, provide a strong rationale for developing this drug class as a treatment for posttraumatic stress disorder.
Mayo 2020 at Abstract.
Since Compound A, i.e., an exemplified embodiment of a compound encompassed by claim 1, is a bioisosteric equivalent of the Example 5 compound of EP ’508 (i.e., PF-04457845), it would be obvious to use it for the same purposes as taught by Mayo 2020, namely in a method of treating post-traumatic stress disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to any one of claim 1.
Furthermore, while the EP ’508, Brown 2012, WO ’949, Johnson 2011 and Mayo 2020 do not teach a method of treating an autism spectrum disorder or post-traumatic stress disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to any one of claim 1, one of ordinary skill in the art would have a reasonable expectation of success in using such a composition in a method for treating an autism spectrum disorder in a subject in need thereof, because the Example 5 compound of EP ’508 was used in such a manner. For example, see Doenni 2016.
Doenni 2016 teaches the administration of PF-04457845 in female Sprague Dawley rats:
Oral administration of the FAAH inhibitor PF-04457845 (1 mg/kg) prior to the social interaction task normalizes LPS-induced alterations in social behavior, while not affecting social behavior in the control group. Infusion of 10 ng PF-04457845 into the basolateral amygdala normalized social behavior in LPS injected females. These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.
Doenni 2016 at Abstract.
Since Compound A, i.e., an exemplified embodiment of a compound encompassed by claim 1, is a bioisosteric equivalent of the Example 5 compound of EP ’508 (i.e., PF-04457845), it would be obvious to use it for the same purposes as taught by Doenni 2016, namely in a method of treating an autism spectrum disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to any one of claim 1.
Therefore, claim 19 was prima facie obvious at the time of filing.
Claim 7 and 13 are obvious over EP ‘508 in view of Dubey 2015:
Claims 7 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over EP’508 in view of Sonal Dubey and Pradnya A. Bhosle, “Pyridazinone: an important element of pharmacophore possessing,” Med. Chem. Res., vol. 24, pp. 3579-3598 (2015) (hereinafter “Dubey 2015).
Claim 7 is directed to the pharmaceutical composition according to claim 1, wherein R6 is H and R2 is —C(O)—C1-C6 alkyl—C(O)—R7 or dihydropyridazinone.5
Claim 13 is directed to the pharmaceutical composition according to claim 1, wherein the compound of Formula (I) is the compound referred to as “Compound B” in the Specification of the instant application, e.g., at [0051], or a pharmaceutically acceptable salt or solvate thereof. Compound B is reproduced below:
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Compound B reads on the “wherein R6 is dihydropyridazinone” element of claim 7, as the examiner interprets the 6-oxo-1,4,5,6-tetrahydropyridazin-3-yl group as an example of a dihydropyridazinone.
EP ’508 is relied upon as above to teach the Example 5 compound of EP ’508, its use in a composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof; and at least one pharmaceutically acceptable excipient.
While the Example 5 compound of EP ’508 is identical to the exemplified embodiment of the instant claims (see Compound B above) except for the 6-oxo-1,4,5,6-tetrahydropyridazin-3-yl group in Compound B which replaces the pyridazin-3-yl group in Example 5 compound of EP ’508, one of ordinary skill in the art would have a reasonable expectation of success in substituting the 6-oxo-1,4,5,6-tetrahydropyridazin-3-yl group for a pyridazin-3-yl group because pyridazinones, a class of molecules of which the 6-oxo-1,4,5,6-tetrahydropyridazin-3-yl group belongs to, were known in medicinal chemistry to impart a wide range of pharmaceutical benefits when incorporated into drug substances. For example, see Dubey 2015.
As background, Dubey 2015 teaches:
Pyridazinone, a derivative of pyridazine, was initially exploited in search of cardiovascular drugs and for its use in agrochemicals, but later on this nucleus was found to be associated with plethora of activities.
Dubey 2015 at Abstract, and
In the past, a lot of research work has been done on pyridazinones. This nucleus is also known as ‘‘wonder nucleus’’ as it has given many compounds with a varied range of pharmacodynamic profile….
Dubey 2015 at 2579.
In its review of the literature surrounding the incorporation of pyridazinones in the chemical structure of drug substances, Dubey 2015 identifies multiple drugs that feature the 6-oxo-1,4,5,6-tetrahydropyridazin-3-yl pharmacophore. For example, Dubey 2015 provides the structure of the following drugs which incorporate the similar dihydropyridazinone motif:
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Dubey 2015 at 3580, and
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Dubey 2015 at 3581.
Dubey 2015 further provides examples of drug substances incorporating pyridazinones that possess qualities that overlap with those reported for the Example 5 compound of EP ’508, such as analgesic, anti-inflammatory, antihypertensive, antidepressant-anxiolytic, qualities and activity for neurological disorders. See Dubey 2015 at 3579 (last paragraph) – 3580.
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990). See also MPEP § 2144.09.
One having ordinary skill in the art at the time of the claimed invention would have found it obvious to substitute a pyridazinone, an in particular the dihydropyridazinone (6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) group for the pyridazin-3-yl group in Example 5 compound of EP ’508, because Dubey 2015 discloses that incorporating pyridazinones as a pharmacophore in a drug substance can impart a wide range of pharmaceutical benefits. The skilled artisan would have been motivated to select the pyridazin-3-yl group of the Example 5 compound of EP ’508 for substitution because Dubey 2015 teaches that pyridazinones are a derivative of pyridazines. Having very close structural similarities to the Example 5 compound of EP ’508, it would be obvious to use the 6-oxo-1,4,5,6-tetrahydropyridazin-3-yl substituted compound for the same purposes, namely in a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof, with at least one pharmaceutically acceptable excipient, as taught by EP ’508. There would have been a reasonable expectation of success, because Dubey 2015 discloses that incorporating pyridazinones into drug substances imparts them with many beneficial pharmaceutical properties that overlap with those reported for the Example 5 compound of EP ’508.
Therefore, claims 7 and 13 were prima facie obvious at the time of filing.
Claim 14 is obvious over EP ‘508 in view of Ahn 2011:
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over EP’508 in view of Ahn et al., “Mechanistic and Pharmacological Characterization of PF-04457845: A Highly Potent and Selective Fatty Acid Amide Hydrolase Inhibitor That Reduces Inflammatory and Noninflammatory Pain,” The Journal of Pharmacology and Experimental Therapeutics, vol. 338, no. 1, pp 114-124 (2011) (hereinafter “Ahn 2011”).
Claim 14 is directed to the pharmaceutical composition according to claim 1, wherein the compound of Formula (I) is the compound referred to as “Compound C” in the Specification of the instant application, e.g., at [0052], or a pharmaceutically acceptable salt or solvate thereof. Compound B is reproduced below:
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EP ’508 is relied upon as above to teach the Example 5 compound of EP ’508, its use in a composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof; and at least one pharmaceutically acceptable excipient.
While the Example 5 compound of EP ’508 is identical to the exemplified embodiment of the instant claims (see Compound C above) except for the 4-oxo-butanoic acid group in Compound C which replaces the pyridazine-3-yl group in the Example 5 compound of EP ’508, one of ordinary skill in the art would have a reasonable expectation of success in substituting the 4-oxo-butanoic acid group for a pyridazin-3-yl group because substitution with the 4-oxo-butanoic acid group would: 1) not be expected to interfere with the known mechanism of human FAAH enzyme inhibition that results in inactivation of human FAAH by the Example 5 compound of EP ’508, and 2) allow for tuning of the various physiochemical properties of the resulting compound. For example, see Ahn 2011.
Ahn 2011 provides the schematic mechanism of covalent, irreversible inhibition of FAAH by PF-04457845 (i.e., the Example 5 compound of EP ’508):
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Anh 2011 at 117.
As taught by Anh 2011, PF-04457845 interacts with the catalytic triad Ser241-Ser217-Lys142 and proceeds to carbamylate the FAAH enzyme, resulting in the irreversible inhibition of FAAH and release of 3-pyridazinamine.
A person having ordinary skill in the art would have a reasonable expectation of success in replacing a 4-oxo-butanoic acid group for the pyridazine-3-yl group in the Example 5 compound of EP ’508, because the 4-oxo-butanoic acid group would be expected to act as a leaving group to form succinamic acid in the same manner as the 3-pyridazinamine group of the Example 5 compound of EP ’508 leaves to form 3-pyridazinamine. The skilled artisan would be motivated to select the pyridazin-3-yl group of the Example 5 compound of EP ’508 for replacement because substituting that group with another group that may function equally well as a leaving group would allow tuning of the various physiochemical properties of the resulting compound, such as in the lipophilicity, solubility, and overall metabolic stability of the drug product.
Therefore, claim 14 was prima facie obvious at the time of filing.
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 of the instant application is not patentably distinct from claim 8 of the ’052 patent:
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 8 of U.S. Patent No. 8,044,052, issued October 25, 2011, assigned to Jazz Pharmaceuticals Therapeutics, Inc. on August 7, 2025 (hereinafter “the ’052 patent”) in view of Brown 2012 and WO ’949.
As discussed above, claim 1 of the instant application is directed to compositions comprising a benzylidine piperidine substituted urea compound of Formula (I), and encompasses one disclosed compound, for example, Compound A:
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Claim 8 of the ’052 patent claims a pharmaceutical composition comprising N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
As explained supra, the compound named in claim 8 of the ’052 patent is also referred to as the Example 5 compound of EP ’508 (as well as PF-04457845). As further explained above, the exemplified embodiment of the instant claim 1 (see Compound A above) was prima facie obvious over the Specification of EP ’508, and in particular the structure of the Example 5 compound of EP ’508 in view of Brown 2012 and WO ’949.
Because the named compound in claim 8 of the ’052 patent and the Example 5 compound of EP ’508 are identical, the same analysis applies. However, while claim 8 of the ’052 patent does not specify that the claimed pharmaceutical composition comprise solvates of the named compound, one having ordinary skill in the art would have a reasonable expectation of success in preparing such solvates because WO ’949 taught that such solvates were forms of the compounds that WO ’949 disclosed, such as the WO ’949 methyl analog. For example, WO ’949 explains:
The compounds described and specifically named herein may form pharmaceutically acceptable complexes, salts, solvates and hydrates.
WO ’949 at 11, paragraph 4.
Since the compound named in claim 8 of the ’052 patent is a bioisosteric equivalent of the WO ’949 methyl analog, it would be obvious to use it the same forms as taught by WO ’949, namely as a solvate.
Therefore, claim 1 of the instant application is not patentably distinct from claim 8 of the ’052 patent.
Conclusion
No claim is found to be allowable.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Compound A is selected as the compound of Formula (I) in pending claim 9 of the instant application.
2 Examples 1 and 2 on page 43 refer to enantiomers of the methyl analog compound possessing (E) stereochemistry. See WO ’949 at 32.
3 Compare hFAAH kinact/Ki values for the Example 5 compound of EP ’508, 24700 M-1s-1, EP ’508 at 82, and the WO ’949 methyl analog, 4590, 3120, 683, 495, 254 M-1s-1, WO ’949 at 43-45, discussed supra.
4 WO ’949 does not assign the R/S nomenclature to the enantiomers of Examples 1 and 2, described in WO ’949 at page 32.
5 Claim 1 defines R7 as hydrogen, halogen, —C1-C6 alkyl, —OH, —O-C1-C6 alkyl, or —O—haloalkyl.