DETAILED ACTION
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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 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, Application No. 63/221,920, 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. A claim by claim analysis indicated a lack of support for: Formula (I) specifically V and it specific substitution, compounds of claims 45, 46, 47, cardiac fibrosis and other diseases such as Huntington’s disease, binding affinity, are not found in Application No. 63/221,920 and so a date of 07/14/2022 was used for priority of claims 1-2, 6, 7, 8, 9, 10, 11, 17, 18, 19, 20, 21,23, 25, 26, 27, 28, 29, 33, 44, 45, 46, 47. Claims 5 and 22 receive a priority date of 07/14/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/01/2025 is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - The “Sequence Listing XML” has not been entered into the application because the required statement of no new matter, in accordance with 37 CFR 1.835(a)(4) or 1.835(b)(5), is missing.
Required response - Applicant must submit a statement that the “Sequence Listing XML,” identified by the date the “Sequence Listing XML” was filed, includes no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink (http://ebookcentral.proquest.com/lib/northeastern ebooks/detail.action?docID=3378734, (page 117)) and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term GraphPad Prism (page 82), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1-2, 6-11, 17-21, 23, 25-29, 33, 44-47 are objected to because of the following informalities: it is unclear why there is a little x in the following figures in claim 1 and 33 as it is never mentioned. Appropriate correction is required.
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Claim Interpretation
All claims read on:
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A person of ordinary skill in the art would know that a compound must be a single stereoisomer and thus this must always be 100% of a single stereoisomer, as the claims state a compound comprises not a composition comprises. Thus the claims have been interpreted as such – to read on a single stereoisomer.
Claims 6-11 and 17, 25 require compounds of formula (I) wherein the compound have specific biological activity as described in claims 6-11 and 17 . The specification and the claims do not provide any direction on what compounds of formula (I) would have this specific activity other than: “The data reveal that aryl substituted 4-PATs are potent 5-HT2A-preferring 5-HT2a/5-HT2cR inverse agonists with selectivity over 5-HTnB and H1Rs” (page 31) and “The present technology provides novel 4-phenyl-2-dimethylaminotetralin (4-PAT) compounds that are shown to provide inverse agonism at one or more 5-HT2A-C receptors. The compounds do not cause sedation at doses that are antipsychotic. The technology demonstrates mechanisms that can be predictive of the selective efficacy of substituents and stereochemistry of 4-PAT compounds. The technology also provides novel serotonin receptor modulating compounds that do not substantially accumulate in the brain (or CNS) and therefore are useful in treating diseases or disorders of the periphery. The technology can be further summarized by the following list of features. 1. A compound for selective modulation of one or more of serotonin 5-HT2A and 5-HT2C receptors, the compound having a structure according to Formula I...”(page 2) and a few examples. Thus to examine the claims, without further direction on which compounds of formula (I) would have this these activities it is assumed that any compound of formula (I) would hold these properties as inherent to the compound.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 23, 25, 27-29 and 46 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 treating specific diseases regulated by serotonin 5-HT2A and 5-HT2C receptors such as psychosis, fragile X syndrome, autism, substance use disorder, and impulsive behaviors, psychosis, fragile X syndrome, autism, substance use disorder, and impulsive behaviors, hypertension, migraine, obesity, irritable bowel syndrome, Parkinson's disease, attention deficit hyperactivity disorder, anxiety or generalized anxiety, depression, schizophrenia, binge eating, opioid use disorder, amphetamine use disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, pain, Alzheimer's disease, or Huntington's disease, hypertension, thrombosis, deep vein thrombosis, pulmonary embolus, atrial fibrillation, atherosclerosis, valvular atherosclerosis, cardiac fibrosis, obesity, irritable bowel syndrome, and lack of bladder control, does not reasonably provide enablement for a method to aid in treating any disease or disorder, or treating psychosis, fragile X syndrome, autism, substance use disorder, and impulsive behaviors, psychosis, fragile X syndrome, autism, substance use disorder, and impulsive behaviors, hypertension, migraine, obesity, irritable bowel syndrome, Parkinson's disease, attention deficit hyperactivity disorder, anxiety or generalized anxiety, depression, schizophrenia, binge eating, opioid use disorder, amphetamine use disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, pain, Alzheimer's disease, or Huntington's disease, hypertension, thrombosis, deep vein thrombosis, pulmonary embolus, atrial fibrillation, atherosclerosis, valvular atherosclerosis, cardiac fibrosis, obesity, irritable bowel syndrome, and lack of bladder control not associated with regulation by serotonin 5-HT2A and 5-HT2C receptors. 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.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. The specification does not provide sufficient information that all diseases are treatable with pharmaceutical composition comprising compound of Formula I described in the method claims.
The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
(1). The Nature of the Invention:
AII of the rejected claims are drawn to an invention which pertains to a method of treatment of a disease by administering a pharmaceutical composition comprising compound of Formula I. The nature of the invention is complex in that it encompasses the treatment of all diseases comprising administering a pharmaceutical composition comprising a compound of Formula I
(2). Breadth of the Claims:
The claims are very broad. The claims would reasonably encompass any disease which could be the treatment of unknown diseases by administering a pharmaceutical composition comprising compound of Formula I. The coverage of diseases in the claim is immense. The breadth of the claims includes hundreds of diseases such as inflammatory, cancers or immunomodulatory or asthma or osteoperosis, etc.
(3). Guidance of the Specification /(4). Working Examples::
The guidance given by the specification as to how one would administer the claimed compounds to a subject in order to treat any disease is Iimited. All of the guidance given by the specification is using selected compounds to regulate serotonin 5-HT2A and 5-HT2C receptors. See pages 76-144 of specification.
There are no working examples for the treatment of any disease using pharmaceutical compositions comprising compounds of Formula (I).
(5). State of the Art:
While the state of the art is relatively high with regard to treating specific disease, the state of the art with regard to treating any disease is underdeveloped. In particular, there is no known compound which is effective against all diseases. For example, there are compounds that treat a range of diseases, but no one has ever been able to figure out how to get a compound to be effective against any disease generally. Thus, the existence of such a ''silver bullet'' is contrary to our present understanding in pharmaceutical art. This is true in part because diseases arise from a wide variety of sources, such as viruses (e.g. EBV, HHV-8, and HTLV-I), exposure to chemicals such as tobacco tars, genetic disorders, ionizing radiation, and a wide variety of failures of the body's cell growth regulatory mechanisms. For example, various types of cancers have different causative agents, involve different cellular mechanisms, and consequently, differ in treatment protocol. It is known (see Jin et al., Nature Reviews Drug Discovery | Volume 22 | March 2023 | 213–234) in the current art that the challenge of cancer treatment has been to target specific therapies to pathogenetically distinct tumor types, to maximize efficacy and minimize toxicity.
(6) The predictability or unpredictability of the art:
The invention is directed to treatment of any disease in general. It is well established that ''the scope of enablement various 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 (1970).
In the instant case the unpredictability of the art is very high because there are thousands of diseases which have fundamentally different mechanism and different causes. The method of diagnosing or treating one disease or condition does not necessitate the treatment or diagnosis of another disease or condition since diseases and conditions have unique chemical pathways by which they are expressed. Additionally, a single disease or condition can be diagnosed via multiple biochemical pathways and treated via multiple biochemical pathways. Thus, the treatment and diagnosis of diseases and conditions is highly unpredictable.
(7). The Quantity of Experimentation Necessary:
In order to practice the claimed invention, one of skill in the art would have to first envision a combination of a compound of Formula I with an appropriate pharmaceutical carrier, a dosage for each, the duration of treatment, route of treatment, etc. and, in the case of human treatment, an appropriate animal model system for one of the claimed compounds. One would then need to test the combination in the model system to determine whether or not the combination is effective. If unsuccessful, one of skill in the art would have to then need to envision a modification of the combination of the compound with an appropriate pharmaceutical carrier, compound dosage, duration of treatment, route of administration, etc. and appropriate animal model system, or envision an entirely new combination of the above and test the system again. In order to practice Applicant's invention, it would be necessary for one to conduct the preceding experimentation for each type of disease because there is no known drug effective for treating all types of diseases. Therefore, it would require undue, unpredictable experimentation to practice the claimed invention to treat any disease in a mammal by administration of a pharmaceutical composition of Formula I.
(8) The quantity of experimentation necessary:
Since every disease and disorder has its unique chemical pathway of expression, diagnosis and treatment of individual diseases and condition cannot be predicted a priori but must be determined from case to case by painstaking experimental study and when the above factors are weighed together, one of ordinary skill in the art would be burdened with undue ''painstaking experimentation study'' to determine which compounds of Formula I treats which diseases/conditions. For example, chemical modification of biomolecules may alter the biological property that is important in the use of that particular, and also other properties such as solubilities in aqueous media, binding affinities etc. Thus variety of compounds encompassed by structure (I) will have different biological properties. Considering variety of compounds covered by Formula I and the multitude of different diseases to be treated, this is a very large degree of experimentation.
Genetech, 108 F.3d at 1366 states that “a patent is not a hunting Iicense. It is not a reward for search, but compensation for its successful conclusion'' and ''[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.''
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.
Claims 1-2, 5-11, 17-21, 22-23, 25-29, 33, 44-47 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.
All claims read on:
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A person of ordinary skill in the art would know that a compound must be a single stereoisomer and thus this must always be 100% of a single stereoisomer, as the claims state a compound comprises not a composition comprises. Thus the claims have been interpreted as such – to read on a single stereoisomer. However, the at least 50% makes the scope of the claim unclear because it would be unclear to one of ordinary skill in the art how a compound would be less than 100% of an individual isomer?
In addition, the scope of claims 22 and 45 are unclear because it is unclear if the compounds mention can comprise additional groups due to the comprises language.
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.
Claim 5 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 5 improperly broadens claim 1 from which it depends because it includes the compounds shown below that are not covered by claim 1 because they have halogen as the Y group.
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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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1-2 and 5-11, 17-18 is/are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by STN (STN CAS 2328044-97-7 REGISTRY, 10 Jun 2019).
The reference STN teaches the following compound, wherein Y= unsubstituted phenyl.
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“Products of identical chemical composition cannot have mutually exclusive properties.” Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F. 2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)
This anticipates claims 1-2 and 5-11, 17-18.
Claim(s) 1-2, 5-11, 17-18, 23, 25 and 26-29 is/are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Sakhuja (R. Sakhuja. et al., / Bioorg.Med.Chem.23 (2015) 1588–1600) as evidenced by Booth (Booth, Raymond, US 20100305212 A1, 2010-12-02).
The reference Sakhuja teaches the following compound(trans-4-(Biphenyl-3-yl)-N,N-dimethyl-1,2,3,4-tetrahy dronaphthalen-2-amine (5n)(section 7.1.4.14)), wherein Y= unsubstituted phenyl (scheme 2).
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The reference Sakhuja also teaches 100% RS and SR stereoisomers of 5n compound and their biological activity. The reference Booth provides evidence that the trans (±) are the RS and SR stereoisomers of the PAT derivatives (chart 1). The reference Sakhuja teaches the pure forms or the 100% of a single stereoisomer in Table 1 (shown below).
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The reference Sakhuja also teaches “Likewise, both enantiomers of the 4-(30-phenyl)-PAT analog (5n) had higher affinity at 5-HT2 over H1 receptors”(page 1591).
The instant application states “The data reveal that aryl substituted 4-PATs are potent 5-HT2A-preferring 5-HT2a/5-HT2cR inverse agonists with selectivity over 5-HTnB and H1Rs” (page 31).
“Products of identical chemical composition cannot have mutually exclusive properties.” Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F. 2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
This anticipates claims 1-2, 5-11, and 17-18.
The reference Sakhuja also teaches “These studies were under taken to facilitate design and development of drugs to treat the cognitive dysfunction common to a variety of neuropsychiatric disorders, including, psychoses, depression, dementia, as well as, substance abuse, attention-deficithy peractivity, and other compulsive behavioral disorders”(page 1589).
This anticipates claims 23, 25, 26-29.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1-2, 5-6, 8, 10, 17-23 and 26-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over BOOTH ( BOOTH, RAYMOND, US 2015315127 A1, 2015-11-05).
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The reference BOOTH teaches the following compound[0236], wherein Y= unsubstituted phenyl and teaches “All enantiomers, diastereomers, racemates, racemic mixtures, enantioenriched mixtures, and diasteromeric mixtures of any of the compounds delineated above are contemplated by the invention”[0242].
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This helps to teach claims 1-2, 5 and claim 22.
The reference BOOTH teaches “In another aspect, the compounds herein are antagonists as well as inverse agonists at serotonin 5HT2A and 5HT2B receptors”[0163]. This helps to teach claims 6 and 18 and 29.
The reference BOOTH teaches “In another aspect, the invention provides a method of treating obesity in a subject, comprising administering to the subject identified as in need thereof a compound capable of selectively inhibiting the 5-HT2c relative to 5-HT2a or 5-HT2b. In certain embodiments, the binding interaction the for inhibiting 5-HT2c is at least 5-fold (alternatively at least 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 500 fold) greater than for either 5-HT2a or 5-HT2b. In certain embodiments, the binding interaction for inhibiting 5-HT2c is at least 100-fold greater than for either 5-HT2a or 5-HT2b”[0046] and “In certain embodiments, the disorder is a neuropsychiatric disorder (e.g., obesity, addiction, cocaine addiction, amphetamine/methamphetamine addiction, anxiety, depression, schizophrenia, and sleep disorders), a neurodegenerative disorder (e.g., Parkinson's Disease, Alzheimer's Disease), a neurological disorder (e.g., epilepsy), a cardiovascular disorder (e.g., hypertension), a gastrointestinal disorder (e.g., irritable bowel syndrome), or a genitor-urinary tract disorder (e.g., bladder control). In certain embodiments, the disorder is psychostimulant (e.g., cocaine, amphetamine, methamphetamine) drug addiction. In certain embodiments, the disorder is obesity. In certain embodiments, the disorder is cognitive dysfunction. In other embodiments, the disorder is allergy or inflammatory disorders”[0044]. This helps to teach claims 8 and 17-18.
The reference BOOTH teaches “In another embodiment, the compounds herein are antagonists as well as inverse agonists at histamine H1 receptors linked to PLC/IP signaling” [0164]. This helps to teach claim 10.
The reference BOOTH teaches “In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like” [305]. This helps to teach claim 19.
The reference BOOTH teaches “In another aspect, the invention provides a method of treating a subject suffering from or susceptible to a neuropsychiatric disorder, including obesity, addiction, cocaine addiction, amphetamine/methamphetamine addiction, psychosis, anxiety, sleep homeostasis. The method includes administering to a subject agonizing 5-HT2c”[0019]. This helps to teach claim 20-21, 26-27.
The reference BOOTH teaches “The term “subject” includes organisms which are capable of suffering from a disorder herein or who could otherwise benefit from the administration of a compound of the invention of the invention, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from a neuropsychiatric disorder or associated state, as described herein. The term “non-human animals” of the invention includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, e.g., sheep, dog, cow, chickens, amphibians, reptiles, etc”[0227] and
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This helps to teach claim 23 and 28.
The reference teaches “Results of structure-activity relationship (SAR) studies indicate that affinity selectivity of the invention compounds for H1 vs. 5HT2A vs. 5HT2B vs. 5HT2C , vs, M1 vs. M2 vs. M3 vs. M4 vs. M5 GPCRs is dependent on the stereochemistry of the substituents at the C1 (e.g., pendant phenyl or other aromatic, heteroaromatic, cyclyl, cycloalkyl) and C3 (amine) positions and, the chemical nature of the C1 and C3 substituents, as well as, the chemical substituents at the C6 and C7 positions of the tetrahydronapthalene ring system (carbon numbering as in Formula I, Table 1). Likewise, agonist vs. inverse agonist vs. antagonist activity at H1 vs. 5HT2A vs. 5HT2B vs. 5HT2C , vs, M1 vs. M2 vs. M3 vs. M4 vs. M5 GPCRs is determined by the chemical nature and stereochemistry of the substituents(s) at C1, C3, C6, and C7. See, e.g., Bucholtz, E. C., Wyrick, S. D., Owens, C. E., and Booth, R. G. 1-Phenyl-3-dimethylaminotetralins (PATs): Effect of stereochemistry on binding and function at brain histamine receptors. Medicinal Chemistry Research 8:322-332 (1998).; Bucholtz, E. C., Brown., R. L., Tropsha, A., Booth, R. G, and Wyrick, S. D. Synthesis, Evaluation and Comparative Molecular Field Analysis of 1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as Ligands for Histamine H1 Receptors. Journal of Medicinal Chemistry. 42:3041-3054 (1999); Choksi, N. Y., Nix, William B., Wyrick, S. D., and Booth, R. G. A novel phenylaminotetralin recognizes histamine H1 receptors and stimulates dopamine synthesis in vivo in rat brain. Brain Research 852:151-160 (2000); Booth R G, Moniri N H, Bakker R A, Choksi N Y, Timmerman H, and Leurs R. A novel phenylaminotetralin radioligand reveals a sub-population of histamine H1 receptors. Journal of Pharmacology and Experimental Therapeutics 302:328-336 (2002); Moniri N H, Covington-Strachan D, Booth R G. Ligand-directed functional heterogeneity of histamine H1 receptors: Novel dual-function ligands selectively activate and block H1 -meditated phospholipas C and adenylyl cyclase signaling. Journal of Pharmacology and Experimental Therapeutics, 311:274-281 (2004); Booth R G, Moniri N H. Ligand-directed multifunctional signaling of histamine H1 receptors Inflammation Research 54: S44-45 (2005); Ghoneim O M, Legere J A, Glbraikh A, Tropsha A, Booth R G. Novel ligands for the human histamine H1 receptor: Synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes. Bioorganic and Medicinal Chemistry, 14:6640-6658 (2006); Booth R G, Moniri N H. Novel Ligands Stabilize Stereo-Selective Conformations of the Histamine H1 Receptor to Activate Catecholamine Synthesis. Inflammation Research 56:1-12 (2007)”[0159]. This helps to teach all claims.
The reference BOOTH does not specifically teach the stereoisomers of the compounds of formula I (all claims).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified BOOTH to achieve the correct stereoisomers because Booth contemplate them [0242] and because compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). One would be motivated to produce and use the other stereoisomers because they are known to affect the biological activity [0159]. One would have a reasonable expectation of success because they are contemplated by the specification and there are a limited number of possibilities.
Claim(s) 33 and 44-47 is/are rejected under 35 U.S.C. 103 as being unpatentable over BOOTH ( BOOTH, RAYMOND, US 2015315127 A1, 2015-11-05) in view of BOOTH(BOOTH, RAYMOND, US2018125798A1, 2018-05-10).
The reference BOOTH 2015 has been discussed supra (and is incorporated by reference herein) and does not disclose the quaternary amine of claims 33 and 44-47.
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The reference BOOTH 2018 teaches 5-HT receptor modulator have the structure of formula II[0002-0008].
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The reference BOOTH 2018 “For clarity, with reference to WO 2008/156707, the present compounds and compositions include derivatives at position R1 of formula (I) therein, which is a genus of 4-PAT compounds. For instance, R1 of formula (I) of WO 2008/156707, as well as compounds PAT #1-31 (e.g. page 21 of WO 2008/156707, the contents of which are hereby incorporated by reference in their entirety) is, in the present invention, an amino group bearing three substituents described herein (e.g. three methyl groups) and therefore a positive charge. In some embodiments, such compounds may agonize 5-HT2c . In some embodiments, such compounds may antagonize 5-HT2a and/or 5-HT2b”[0028] and “Compounds Bearing a Positively Charged Amino Group at the 2 Position of the Tetralin Core do not Readily Cross the Blood-Brain Barrier” using mice subjects (page 16). The reference also teaches “The present invention is based, in part, on the discovery of novel serotonin receptor-modulating compounds that do not substantially accumulate in the brain and therefore are useful in treating diseases or disorders of the periphery, including gastrointestinal or cardiopulmonary disorders or conditions”[0016] and “In some aspects, the present invention relates to method for treating or preventing a gastrointestinal disorder or condition, optionally selected from inflammatory bowel disease, irritable bowel syndrome, celiac disease, and an enteric infection, comprising administering the compound or composition described herein to a patient in need thereof”[0013].
This helps to teach claims 33, 44, 45, 46 and 47.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified BOOTH 2015 with BOOTH 2018 because both teach 5-HT receptor modulator with very similar structure for the same purpose of treating gastrointestinal disorder or conditions. One would be motivated to modify the lead structure of BOOTH 2015 with the positively charged amino groups taught by BOOTH 2018 so that serotonin receptor-modulating compounds will not substantially accumulate in the brain and therefore are useful in treating diseases or disorders of the periphery, including gastrointestinal diseases. One would have a reasonable expectation of success because there is only minor difference in structure between the two references.
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.
Claims 1-2, 5-6, 8, 10, 17-23, 26-29, 33 and 44-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US 10017458 B2 in view of BOOTH ( BOOTH, RAYMOND, US 2015315127 A1, 2015-11-05) in view of BOOTH(BOOTH, RAYMOND, US2018125798A1, 2018-05-10).
The patent ‘458 claims:
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This helps to teach claims 1-2, 5-6, 8, 10, 17-23, 26-29, 33 and 44-47 .
The reference BOOTH 2015 and 2018 teach that all needed changes would be obvious as outlined in the 103 rejection (which is incorporated herein by reference).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified patent ‘458 with BOOTH to achieve the correct stereoisomers because patent ‘458 teaches the same compounds as Booth and Booth contemplate the stereoisomers [0242] and because compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). One would be motivated to produce and use the other stereoisomers because they are known to affect the biological activity [0159]. One would have a reasonable expectation of success because they are contemplated by the specification and there are a limited number of possibilities.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified patent ‘458 with BOOTH 2015 and BOOTH 2018 because all teach 5-HT receptor modulator with very similar structure for the same purpose of treating gastrointestinal disorder or conditions. One would be motivated to modify the lead structure of BOOTH 2015 with the positively charged amino groups taught by BOOTH 2018 so that serotonin receptor-modulating compounds will not substantially accumulate in the brain and therefore are useful in treating diseases or disorders of the periphery, including gastrointestinal diseases. One would have a reasonable expectation of success because there is only minor difference in structure between the two references.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. US 9422229 B2 and over claims 1-12 of U.S. Patent No. US 8586634 B2 in view of BOOTH ( BOOTH, RAYMOND, US 2015315127 A1, 2015-11-05).
The patent ‘229 claims:
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The patent ‘634 claims:
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This helps to teach claim 5.
The reference BOOTH 2015 teach that all needed changes would be obvious as outlined in the 103 rejection (which is incorporated herein by reference).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified patents ‘229 and ‘634 with BOOTH to achieve the correct stereoisomers because patent patents ‘229 and ‘634 teaches the same compounds as Booth and Booth contemplate the stereoisomers [0242] and because compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). One would be motivated to produce and use the other stereoisomers because they are known to affect the biological activity [0159]. One would have a reasonable expectation of success because they are contemplated by the specification and there are a limited number of possibilities.
Conclusion
Claims 1-2, 5-11, 17-23, 25, 26-29, 33 and 44-47 are rejected.
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/A.A.H./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627
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