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 .
Status of the Claims
Claims 1-13 are pending. Acknowledgment is made of the cancellation of claims 14-20 in the reply filed 09/30/2025.
Domestic Benefit
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. Instant application is a U.S. National Stage Entry of PCT/US2021/035622, filed 06/03/2021. PCT/US2021/035622 claims benefit of U.S. Provisional Application No. 63/034,687, filed 06/04/2020. Therefore, the effective filing date is 06/04/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/08/2023 and 06/17/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Restriction/Election Requirement
Applicant’s election without traverse of Group I, directed to a compound of formula (I) or a composition thereof, in the reply filed on 09/30/2025 is acknowledged. Applicant further elected the species compound 58, shown below, which reads on claims 1-8, 10, 12, and 13. Examination has been limited to the elected species below and any 35 U.S.C. 102 prior art discovered in the search.
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Claims 9 and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/30/2025.
Claim Objections
Claims 5, 10, and 12 are objected to because of the following informalities:
Claim 5 reads “…wherein: R2 is C1-6 alkyl; R3 is …”, and should read “…wherein R2 is C1-6 alkyl and R3 is …” (emphasis added).
Claim 10 reads “…wherein R3 is: … wherein R5 is selected from: -CH(CH3)NHCH2CH2CH3, and piperazinyl.” (emphasis added where comma should be removed) and should read “…wherein R3 is … and wherein R5 is selected from -CH(CH3)NHCH2CH2CH3 and piperazinyl.” (emphasis added).
Rule 1.141(a) states:
Two or more independent and distinct inventions may not be claimed in one national application, except that more than one species of an invention, not to exceed a reasonable number, may be specifically claimed in different claims in one national application, provided the application also includes an allowable claim generic to all the claimed species and all the claims to species in excess of one are written in dependent form (§ 1.75) or otherwise include all the limitations of the generic claim.
Claim 12 claims a large number of species of the generic claim, but in independent format. Multiple inventions may not be claimed in a single application unless they are species claims which are dependent upon the larger, generic claim. In the past, the Office has held a “reasonable number” to be five (5) species. The present claim contains well over this number of species. One could envision forty pages of species compounds in a single claim which is not dependent upon any genus claim. This would cause undue burden to the Office in examining such a large claim. Therefore, it is recommended that claim 12 either be dependent from a larger, genus claim, or, that claim 12 incorporate all of the limitations of the genus claim.
Appropriate correction is required.
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 1-3, 8, and 13 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 compounds of formula (I) where R3 is C1-C8 alkyl, -C1-C8 aminoalkyl, -(CH2)n-phenyl, -(CH2)n-(C3-C7 cycloalkyl), -(CH2)n-(4- to 7-membered monocyclic heterocycloalkyl), or -(CH2)n -(5- or 6- membered monocyclic heteroaryl) and where R7 is C1-6 halo, amino, C1-C6 aminoalkyl, or C1-6 alkyl, does not reasonably provide enablement for compounds of formula (I) where R3 is -CH2-(7- to 10-membered bicyclic heteroaryl), wherein said -CH2-(7- to 10-membered bicyclic heteroaryl) is substituted by one or more R6 substituents, or where R7 is C3-C7 cycloalkyl, -O-(C1-6 alkyl), -O-(C1-6 hydroxyalkyl), -O-(C1-6 alkylene)-C(O)OR8, -O- (C1-6 haloalkyl), C1-6 hydroxyalkyl, halo, 6- to 11-membered spirocyclic bicyclic heterocycloalkyl, -N(R8)2, -(C1-C3 alkylene)-N(R8)2, -( C1-C3 alkylene)-(Ci-C6 aminoalkyl), -(C1-C3 alkylene)-N(CH3)-(C1-C6 aminoalkyl), -NH-(C1-C6 aminoalkyl), RA, RB, and RC. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention
The nature of the invention relates to compounds of formula (I) in claim 1. Such compounds are useful for as TLR7 and TLR8 agonists. This invention is also directed to compositions comprising said compounds.
Predictability of the art
The hypothetical compounds in claim 1 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 1. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
4. The breadth of the claims
The scope of the claims involves compounds of formula (I), shown below.
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Claim 1 is very broad in the number of variables and the options of substituents for each variable. There is an extremely large amount of hypothetical compounds included in claim 1.
5. The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary
In all of the compounds synthesized, there are no examples where R3 is a bicyclic heteroaryl group. Additionally, examples are only provided where R7 is aminoalkyl. However, it would be assumed that the inventors are also enabled for R7 being amino, halo, and alkyl, since these substituents are similar in size and reactivity.
Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. It would be expected that the varying ring sizes (e.g., where R3 is a 10-membered bicyclic heteroaryl) and heteroatoms in the rings (since the claims do not limit the heteroatoms) would change the reactivity of the compounds, and therefore may require alternate synthesis methods. It could also be possible that some combinations of compounds may not be able to be synthesized due to their instability (e.g., steric hindrance from large bicyclic ring systems). Changing the groups on R7 from an alkyl or aminoalkyl to, for example, a 6- to 11- membered spirocyclic bicyclic heterocycloalkyl group, would require alternate synthesis methods not provided by the specification. It would require one skilled in the art, such as a chemist, to perform thousands of reactions to determine which compounds of formula (I) can be prepared and would likely require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 2, 10, and 11 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.
Claim 2 recited that R3 may be (CH2)2-phenyl. However, claim 1 recites that R3 may be (CH2)n-phenyl, where n is 0 or 1. Therefore, claim 2 expands the scope of the claim upon which it is dependent.
Claim 10 recites a compound of claim 6 where R3 is
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. Claim 11 recites a compound of claim 6 where R3 is
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. However, claim 6 recites that R3 is
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or
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. Therefore, claims 10 and 11 add an additional -CH2- group that is not present in the R3 group of claim 6, and expand the scope of the claim upon which they depend. For the sake of compact prosecution, claim 6 will be interpreted as having this additional -CH2- group where R3 is linked to the core structure.
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
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5, 6, 8, and 13 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Poudel et al. (U.S. Patent No. 11,400,094 B2), hereinafter referred to as patent ‘094, with an effectively filed date of 08/03/2018.
Patent ‘094 teaches, in claim 1, compounds of formula (II), shown below.
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Compound IIa-02, shown below from Table A, reads on instant claims 1-3, 5, 6, 8, and 13, where both instances of R1 are H, one instance of R2 is H, the other R2 is n-butyl, R3 is benzyl substituted by two R5 groups, where one R5 is methoxy and the other is -CH2-piperazinyl.
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Claims 1, 3, 8, and 13 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Poudel et al. (US 20200038403 A1), hereinafter referred to as reference ‘403, cited by Applicant in the IDS, with an effectively filed date of 08/03/2018.
Reference ‘403 teaches, in Figure 2B, the compound 19a, shown below.
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This compound 19a reads on instant claims 1, 3, 8, and 13, where both instances of R1 are H, one instance of R2 is H, the other R2 is n-butyl, R 3 is benzyl substituted by two R5 groups, where one R5 is methoxy and the other is hydroxymethyl.
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 4, 7, 10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Poudel et al. (U.S. Patent No. 11,400,094 B2), hereinafter referred to as patent ‘094, as applied to claims 1-3, 5, 6, 8, and 13 above.
Patent ‘094 teaches Compound IIa-02 in Table A. See above rejection.
Compound IIa-02 differs from the elected species in that it is a homolog of the elected species.
The CCPA has defined a homologous series as a family of chemically related compounds, the composition of which varies from member to member by a -CH2 (one atom of carbon and two hydrogen). In re Coes, Jr. (CCPA 1949) 173 F2d 1012, 81 USPQ 369. The Court of Appeals for the District of Columbia applied a broader definition and defined a homolog (homologue) as a member of a series of compounds in which each member differs from the next member by a constant number of atoms. Carr. Pats.v. Deutsche Gold-und-Sllber, etc. (CADC 1968) 397 F2d 656,157 USPQ 549.
The "Hass-Henze Doctrine" evolved from three CCPA cases, viz., In re Hass et al. (CCPA 1944) 141 F2d 122 and 127, 60 USPQ 544 and 548; and In re Henze (CCPA 1950) 181 F2d 198, 85 USPQ 261. In the Henze decision, the Court said:
"The nature of homologues and the close relationship the physical and chemical properties of one member of a series bears to adjacent members is such that a presumption of unpatentability arises against a claim directed to a composition of matter, the adjacent homologue of which is old in the art. The burden is on the applicant to rebut that presumption by a showing that the claimed compound possesses unobvious or unexpected beneficial properties not actually possessed by the prior art homologue. It is immaterial that the prior art homologue may not be recognized or known to be useful for the same purpose or to possess the same properties as the claimed compound. The CCPA concluded that because the characteristics normally possessed by members of a homologous series are principally the same, varying gradually from member to member, chemists knowing the properties of one member of a series would in general know what to expect in adjacent members so that a mere difference in degree is not the marked superiority which will ordinarily remove the unpatentability of adjacent homologues of old substances. Contra, where no use for the prior art compound is known. In m Stemniski (CCPA 1971) 444 F2d 581, 170 USPQ 343, and cases cited therein. Whether a compound is patentable over a prior art homologue or isomer is a question to be decided in each case. In re Hass et al., supra."
The 'Hass-Henze Doctrine" stands for the proposition that, "If that which appears at first blush to be obvious though new is shown by evidence not to be obvious then the evidence prevails over surmise or unsupported contention and rejection based on obviousness must fail." In re Papesch (CCPA 1963) 315 F2d 381, 137 USPQ 43, 48. The presumption that homologues are unpatentably obvious is an inference of fact, viz., that adjacent homologs are expected to have similar properties which places a 'burden of persuasion' on the applicant who asserted a contrary fact. In re Mills (CCPA 1960) 281 F2d 218, 126 USPQ 513.
Compounds that differ only by the presence of an extra methyl group are homologs. Homologs are of such close structural similarity that the disclosure of a compound renders prima facie obvious its homolog. The homolog is expected to be capable of preparation by the same method and to have the same properties. This expectation is then deemed the motivation for preparing homologs. Homologs are obvious even in the absence of a specific teaching to methylate, In re Wood 199 USPQ 137; In re Hoke 195 USPQ 148; In re Lohr 137 USPQ 548; In re Magerlein 202 USPQ 473; In re Wiechert 152 USPQ 249; Ex parte Henkel 130 USPQ 474; In re Fauque 121 USPQ 425; In re Druey 138 USPQ 39. In all of these cases, the close structural similarity of two compounds differing by only one (or two) methyl groups sufficed; no specific teaching to methylate was present or required. None of these cases has been overruled and indeed the examiner is unaware of any post Lohr case in which motivation is required to put a methyl group on an old compound.
Therefore, since the instant elected species is a homolog of a prior art compound, Compound IIa-02, and it is taught to be used for the same purpose as the prior art species, as a TLR7 agonist, the instant elected species is rendered prima facie obvious in view of the prior art.
Conclusion
Claims 1-8, 10, 12, and 13 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RILLA M SAMSELL whose telephone number is (703)756-5841. The examiner can normally be reached Monday-Friday, 9-5.
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/R.M.S./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624