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
The amendments to the claims filed October 22, 2025 are acknowledged and entered. Claims 1-36 are pending.
Priority
This application is a 371 of PCT/US2021/061172, filed November 30, 2021, which claims benefit of 63/121,283, filed December 4, 2020.
Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification.
Information Disclosure Statement
Acknowledgement is made of the Information Disclosure Statements filed on June 18, 2024 and May 14, 2025. All references have been considered except where marked with a strikethrough.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-18, drawn to a compound of Formula I) and the species corresponding to 6-tert-Butyl- 5-(4-chlorophenyl)-4-(2-fluoro-6-(trifluoromethoxy)phenoxy)thieno [2,3-d] pyrimidine (pictured below for convenience) in the reply filed on October 22, 2025 is acknowledged.
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The elected species corresponds to Formula I wherein
X is O; Y is S; R1 is H; R2 is substituted phenyl corresponding to 2-fluoro-6-trifluoromethoxyphenyl; R3 is substituted aryl corresponding to 4-chlorophenyl; R4 is C4 alkyl corresponding to t-butyl. Applicant submits that at least claims 1, 2-5 and 7-14 encompass the elected species.
The guidelines in MPEP § 803.02 provide that upon examination if prior art is found for the elected species, the examination will be limited to the elected species. Relevant portion of MPEP § 803.02 is provided here for convenience:
As an example, in the case of an application with a Markush-type claim drawn to the compound X-R, wherein R is a radical selected from the group consisting of A, B, C, D, and E, the examiner may require a provisional election of a single species, XA, XB, XC, XD, or XE. The Markush-type claim would then be examined fully with respect to the elected species and any species considered to be clearly unpatentable over the elected species. If on examination the elected species is found to be anticipated or rendered obvious by prior art, the Markush-type claim and claims to the elected species shall be rejected, and claims to the nonelected species would be held withdrawn from further consideration. A second action on the rejected claims can be made final unless the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p). See MPEP § 706.07(a).
If the elected species or group of patentably indistinct species is not anticipated by or obvious over the prior art, the examiner should extend the search and examination to a non-elected species or group of species that falls within the scope of a proper Markush grouping that includes the elected species. The search and examination should be continued until either (1) prior art is found that anticipates or renders obvious a species that falls within the scope of a proper Markush grouping that includes the elected species, or (2) it is determined that no prior art rejection of any species that falls within the scope of a proper Markush grouping that includes the elected species can be made. The examiner need not extend the search beyond a proper Markush grouping. In other words, the examiner need not extend the search to any additional species that do not share a single structural similarity and a common use with the elected species (i.e., do not belong to the same recognized physical or chemical class or to the same art-recognized class and/or do not have a common use and/or do not share a substantial structural feature of a chemical compound and a use that flows from the substantial structural feature). The examiner should continue examination of the Markush claim to determine whether it meets all other requirements of patentability (e.g., 35 U.S.C. 101 and 112, nonstatutory double patenting, and proper Markush grouping).
The elected species was not found in the prior art and the search was expanded to include the subgenus of either:
Formula (I) wherein X is O; Y is S or O; and R2 and R3 are independently optionally substituted cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; or
Formula (I) wherein X is O; Y is S or O; and R4 is unsubstituted C1-C4 alkyl. And art was found. Claims 1-14 and 17 read on the expanded subgenus.
Claims 15-16 and 18 (in full) and claims 1-14 and 17 (all in part, other than the above indicated subgenus) are additionally withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species.
Claim Rejections - 35 USC § 112a
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 1-12 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for formula (I) wherein R1 is H and R4 is unsubstituted C1-C4 alkyl does not reasonably provide enablement for all of the R1 and R4 groups claimed.
The specification is not adequately enabling for the scope of the compounds claimed. The only useful compounds are those embodiments disclosed at pages 48-83 (Examples 3-66) of the specification and which are included in the subgenus of formula (I) indicated above. This narrow scope of compounds does not give a reasonable assurance that all, or substantially all of the compounds within the scope of the claim are useful. The claims are not drawn in terms of a recognized genus but are directed to a more or less artificial selection of compounds. There is no reason why a claim drawn in this way should not be limited to those compounds which are shown to be useful. An Applicant is not entitled to a claim for a large group of compounds merely on the basis of a showing that a selected few are useful and a general suggestion of a similar utility in the others. There is no statement of utility beyond modulation of MRGPRX1 (See page 9; Example 66; EC50). Ex parte Lanham, 108 USPQ at 135 states “It was never intended that a patent be granted upon a product, or a process producing a product, unless such product be useful.”
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). These factors include the following:
1) Amount of guidance provided by applicant. The Applicant has demonstrated the embodiments at on pages 48-83 (Examples 3-66) and which are described by the above indicated subgenus of formula (I), are modulators of MRGPRX1 (See page 9; Example 66; EC50). However, there is no evidence to show the full scope of formula (I) which includes thousands of structurally diverse compounds have any use.
2) The nature of the invention and predictability in the art. It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
3) Number of working examples. A compound of formula (I) wherein R1 is H and R4 is unsubstituted C1-C4 alky represents a narrow subgenus for which applicant has provided sufficient guidance regarding how to use. However, this disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts of formula (I) beyond the narrow subgenus indicated above.
Within the specification, “specific operative embodiments or examples of the invention must be set forth, Examples and description should be of sufficient scope as to justify the scope of the claims, Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
4) Scope of the claims. The scope of the claims involves all of the thousands of compounds of the following formula:
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wherein
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Thus, the scope of the claims is very broad.
5) Level of skill in the art. The artisan using applicant' s invention would be a scientist with a Ph.D. degree and having several years of research experience.
6) Undue experimentation. MPEP §2164.01 (a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)."
The conclusion is clearly justified here that applicant is not enabled for using these compounds
Claim Rejections - 35 USC § 112b
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 1-13 and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. [A] claim is indefinite when the boundaries of the protected subject matter are not clearly delineated and the scope is unclear (MPEP 2173.04). The following terms and/or phrases render the scope of the claims unclear because the specification does not provide a scope limiting definition of the phrase or term, or any direction for ascertaining the scope of the limitation indicated by the term or phrase. Accordingly, one skilled in the art could not ascertain the metes and bounds of the claimed invention.
The claims recite the limitation “substituted” (e.g. claim 1 recites R1 is substituted cycloalkyl, substituted aryl, substituted heteroaryl; see also R2, R3 and R4). The limitation “substituted” renders the claims unclear at each occurrence throughout the claims because no substituents are provided in the claim and the specification fails to provide a scope limiting definition of substituents. A person skilled in the art understands the meaning of “substituted”; however, the limitation is unclear because they cannot ascertain the scope of such a group because based on the specification it is not clear which substituents Applicant intends as part of invention. The specification generically defines substitutions as those that comply with the principles of chemical bonding and only a few examples are provided (see pages 28, lines 30-35 to page 29, lines 1-5). Page 29, lines 5-10, teaches “substituent group” includes one or more moiety defined herein; however, there is no clear definition of which substituents are included in the scope of the claims. For this reason, the scope of “substituted” is open to different interpretations and therefore the metes and bounds of the invention cannot be determined by a person skilled in the art. Examiner suggests amending the claims to recite specific substituents which are supported by the specification as filed.
The claims recite the limitation “C3-C7 cycloheteroalkyl”. This limitation renders the scope of the invention indefinite because the cycloheteroalkyl is defined in terms of C number, as opposed to ring size, and the number of heteroatoms is not indicated. Moreover, the specification does not provide adequate direction for ascertaining the metes and bounds of the limitation as the provided definition is open ended (see definition at pages 31-32). Therefore the structure of such a ring has no clear upper limit for the reason that the number of heteroatoms is not specified. The limitation is open to different interpretations. Examiner suggests amending the claim to clarify the size of the ring (e.g. C3-C7 cycloheteroalkyl consisting of 1-2 N atoms).
The claims recite “aryl” which renders the scope of the claim indefinite because it is not clear from the claim, nor the specification, which aryl groups Applicant intends. A person skilled in the art understands what “aryl” means generally; however, the specification teaches “aryl” includes single or multiple rings without providing any upper limit as to ring size or possible number of rings. The scope of what Applicant intends as “aryl” is not clear. The limitation would be more clear if amended to recite specific ring sizes or aryl rings for which Applicant has written support.
The claims recite the limitation “arylalkyl”. This limitation is indefinite because the size of “alkyl” is not specified in the claim, or in the definition provided in the specification. The structure of an arylalkyl group is therefor unclear as the size or length of the “alkyl” is not specified and thus open to different interpretations.
The claims recite the limitation “heteroaryl”. The specification defines “heteroaryl” as an aryl group that contains from one to four heteroatoms (see page 34, lines 10-15). The limitation is indefinite because it depends on the definition of “aryl” which, as noted above, is unclear. The limitation would be more clear if amended to recite specific heteroaryl groups for which Applicant has written support.
The claims recite R1, R2 or R3 is C1-C4 alkyl (see also R5-8); however, the claim does not require that the C1-C4 alkyl is substituted or unsubstituted. It is unclear if Applicant intends the C1-C4 alkyl to be substituted or unsubstituted for the reason that the specification defines “alkyl” as optionally substituted (see page 30, lines 5-10) and every other limitation in the claims explicitly recites “substituted or unsubstituted” (e.g. R4 is substituted or unsubstituted C1-C4 alkyl). Clarification of what Applicant intends is respectfully requested.
Claims 2-13 and 17 depend from claim 1, do not cure all of the abovementioned deficiencies, and therefore are also indefinite.
Claim 5, final line, recites “C1-C4” without specifying any particular group (e.g. C1-C4 alkyl). The claim should be amended to clarify which group Applicant intends (e.g. C1-C4 alkyl).
Claims 7 recites the limitation “R1 is selected from…amino”. There is insufficient antecedent basis for “amino” because claim 7 depends from claim 1 which does not teach that R1 can be an amino group. Claim 8-12 depend from claim 7, do not cure this deficiency, and therefore are also indefinite.
Claim 13 recites each R9 is..-OF3. Examiner believes Applicant intends “-OCF3” (see page 4 of specification, lines 20-25). Appropriate clarification is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2, 4-5 and 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lampe et al. (CA2685134; published 2008) (hereinafter “Lampe”).
Lampe teaches compound 119 (page 190; pictured below for convenience) which corresponds to instant Formula (I) wherein X and Y are each O; R1 is H; R2 is substituted cycloheteroalkyl (piperidinyl substituted with
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; R3 is aryl (phenyl) substituted with halogen (Cl); and R4 is unsubstituted aryl (phenyl). Examiner notes that Lampe is not included in the proviso (see claim 1, when X and Y are both O…). Therefore compound 119 anticipates the instant invention.
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Claim(s) 1 and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lu et al. (US9,434,741) (hereinafter “Lu”).
Lu teaches compound S-61 (col 12; pictured below for convenience) which corresponds to instant Formula (I) wherein X is O; Y is S; R1 is H; R2 is substituted C1 alkyl (methyl substituted with
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; this group fits the definition of “substituted alkyl” provided at least at page 29 of the specification which is open ended and unclear; see also page 28 lines 30-35 to page 29 lines 1-5: substitutions are selected so as to comply with principles…for example heteroaryl); R3 is H; and R4 is C4 alkyl (t-butyl). Examiner notes that compound S-61 is not included in the proviso (see claim 1, when X is O and Y is S…). Therefore compound S-61 anticipates the instant invention.
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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.
Claim(s) 1 and 2-3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lampe et al. (CA2685134; published 2008) (hereinafter “Lampe”).
Lampe teaches a generic group of compounds which embraces applicants’ claimed compounds (See Formula (I), pages 4-7) for use as pharmaceuticals and compositions (page 233) for the treatment of pulmonary hypertension (see claim 12). The claims differ from the reference by reciting specific species and a more limited genus than the reference. However, it would have been obvious to one having ordinary skill in the art before the filing date of the invention to select any of the species of the genus taught by the reference, including those instantly claimed, because the skilled chemist would have the reasonable expectation that any of the species of the genus would have similar properties and, thus, the same use as taught for the genus as a whole. One of ordinary skill in the art would have been motivated to select the claimed compounds from the genus in the reference since such compounds would have been suggested by the reference as a whole. It has been held that a prior art disclosed genus of useful compounds is sufficient to render prima facie obvious a species falling within a genus. In re Susi, 440 F.2d 442, 169 USPQ 423, 425 (CCPA 1971), followed by the Federal Circuit in Merck & Co. v. Biocraft Laboratories, 847 F.2d 804, 10 USPQ 2d 1843, 1846 (Fed. Cir. 1989).”
In particular, Lampe teaches compound 119 which was discussed in the above rejection, the teachings of which are incorporated herein by reference. Lampe further teaches a genus of Formula (I) (page 4; pictured below for convenience) which instructs that the piperidinyl group of compound 119, which corresponds instant R2, may be further substituted with a halogen atom (page 16, lines 20-25: Of very particular importance…Q represents piperidinyl; page 17, lines 1-5: may be substituted by…fluorine). Lampe thus teaches wherein the group corresponding to R2 of the instant claims can be substituted with a halogen as required by the present invention.
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The difference between the prior art and the instant claims is that the instant claims require wherein R2 is substituted with one or more halogen atoms. However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to modify compound 119 of Lampe into the claimed invention because Lampe had specifically disclosed the modification.
One would have been motivated as a matter of making additional compounds for treating pulmonary hypertension.
One would have had a reasonable expectation of success because Lampe specifically disclosed that the group corresponding to R2 of the instant claims could be substituted with halogen. One therefore could have reasonably expected that such a modification would result in a compound with similar activity to compound 119.
Allowable Subject Matter
Claim 13 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Claim 14 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The closest reference to the instant claims is Lu et al. (US9,434,741) which was discussed in the rejection herein. The difference between Lu and the instant claims is that instant claims require instant R2 and/or R3 to be cycloalkyl, cycloheteroalkyl, aryl or heteroaryl. Lu does not teach these groups which are required by the claims. There is no teaching which would have motivated one of ordinary skill in the art before the effective filing date of the instant application to modify Lu into the claimed invention with any reasonable expectation of success.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN MARTIN whose telephone number is (571)270-0917. The examiner can normally be reached Monday - Friday 8 am - 5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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December 5, 2025
/K.S.M./Examiner, Art Unit 1624
/BRUCK KIFLE/Primary Examiner, Art Unit 1624