DETAILED ACTION
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 1-16, 21, 22, 24, and 26 are pending. Claims 17-20, 23, and 25 are cancelled. Claims 2-6, 9-16, 24, and 26 are withdrawn as explained in the “Election/Restrictions” section below.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/US2022/023110, filed on April 1, 2022. This application also claims the benefits of priority to U.S. Provisional Application no. 63/170,561, filed on April 4, 2021.
Information Disclosure Statement
The following was listed in the IDS:
WO 2019110352 A1
However, Examiner could not locate the corresponding document in the application file wrapper and, thus, the reference was not considered.
Election/Restrictions
As a reminder, Applicant elected, with traverse, Group I which corresponds to claims 1-16, 21, and 22. Applicant respectfully “requests withdrawal of the restriction requirement because there is no serious burden imposed on the Office if restriction is not required.” However, Examiner respectfully does not find Applicant’s argument persuasive.
According to MPEP § 1896, III. Unity of Invention:
“U.S. national applications filed under 35 U.S.C. 111(a) are subject to restriction practice in accordance with 37 CFR 1.141 -1.146. See MPEP § 803. U.S. national stage applications are subject to unity of invention practice in accordance with 37 CFR 1.475 and 1.499. See MPEP § 1893.03(d).”
In Applicant Remarks (filed April 2, 2026), Applicant refers to MPEP § 803 to support their assertion that a “serious burden on the Office does not exist because the groups of claims may not require distinct searches.” However, this statement is only applicable if the instant application is a U.S. national application filed under 35 U.S.C. 111(a) (as stated in the excerpt above from MPEP § 1896, III. Unity of Invention). Since the instant application is a U.S. national stage application, it is subject to unity of invention practice in accordance with 37 CFR 1.475 and 1.499. See MPEP § 1893.03(d).
Further, according to MPEP § 1850, II. Determination of “Unity of Invention”:
Whether or not any particular technical feature makes a "contribution" over the prior art, and therefore constitutes a "special technical feature," should be considered with respect to novelty and inventive step. For example, a document discovered in the international search shows that there is a presumption of lack of novelty or inventive step in a main claim, so that there may be no technical relationship left over the prior art among the claimed inventions involving one or more of the same or corresponding special technical features, leaving two or more dependent claims without a single general inventive concept.
Lack of unity of invention may be directly evident "a priori," i.e., before considering the claims in relation to any prior art, or may only become apparent "a posteriori," i.e., after taking the prior art into consideration. For example, independent claims to A + X, A + Y, X + Y can be said to lack unity a priori as there is no subject matter common to all claims. In the case of independent claims to A + X and A + Y, unity of invention is present a priori as A is common to both claims. However, if it can be established that A is known, there is lack of unity a posteriori, since A (be it a single feature or a group of features) is not a technical feature that defines a contribution over the prior art.
In the instant case, Groups I-III lack unity of invention because even though the inventions of these groups require the technical feature of a compound of instant formula (I), this technical feature is not a special technical feature as it encompasses compounds that are known and anticipated by the prior art (see restriction requirement submitted by Examiner, dated February 5, 2026 for details).
For these above reasons, the restriction requirement and the species election are maintained and claims 24 and 26 are withdrawn.
Applicant also elected the following species:
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.
It is noted here that according to MPEP §2117, III. Rejection based on improper Markush Group:
“As explained with regard to election of species practice as set forth in detail in MPEP § 803.02, the search need not be extended to species that fall outside a proper Markush grouping.”
And according to MPEP §803.02:
If on examination the elected species is found to be anticipated or rendered obvious by prior art, the Markush claim and claims to the elected species will be rejected, and claims to the nonelected species will be held withdrawn from further consideration.
If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species, and need not be extended beyond a proper Markush grouping.
In the instant case, prior art was found that anticipates and renders obvious the Markush claim with respect to a nonelected species and the elected species was also found obvious (see sections “Claim Rejections - 35 USC § 102” and “Claim Rejections - 35 USC § 103” below for details). As such, claims to nonelected species (i.e., claims 2-6 and 9-16) are held withdrawn from further consideration and only claims 1, 7, 8, 21, and 22 are examined in this office action.
Specification - Abstract
Applicant is reminded of the proper content of an abstract of the disclosure.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class.
Specification - Disclosure
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 errors of which applicant may become aware in the specification.
Claim Objections
Claims 1, 7, 8, and 21 are objected to because of the following informalities:
Claim 1:
For clarity and to avoid 112 issues, claim 1 should read:
“A compound having formula (I)… or a hydrate, solvate, or a pharmaceutically acceptable salt thereof, wherein…”
For consistency:
The last line of claim 1 should end with a period instead of a semicolon.
To be concise:
Redundant terms should be removed as explained below:
The term "C3-7 branched alkyl" given in claim 1 for several substituents (e.g. R¹) appears to be redundant in the presence of the term "C1-6 alkyl" which according to common knowledge as well as to paragraph [0024] of the present description includes straight and branched carbon chains. The same applies to the term "C3-7 branched alkoxy" given in claim 1 for substituent R² which appears to be redundant in the presence of the term "C1-6 alkoxy"
Claims 7 and 8:
For clarity and to avoid 112 issues, claims 7 and 8 should read:
“The compound according to claim 1 having formula… or a hydrate, solvate, or a pharmaceutically acceptable salt thereof.”
Claim 21:
For clarity, consistency, and to avoid 112 issues, claim 21 should read:
“The compound according to claim 1 selected from the group consisting of:(S)-9-(carboxymethoxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido [2,1-a]isoquinoline-3-carboxylic acid;…
(S)-9-((7-carboxyheptyl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid; and(S)-9-((8-carboxyoctyl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acidor a hydrate, solvate, or a pharmaceutically acceptable salt thereof.
Appropriate correction is required.
Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Rejections – Improper Markush Grouping
Claims 1, 7, and 22 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) the species of the Markush group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the Specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
The claimed Markush group encompasses compounds having substantially different core structures. Some examples are depicted below:
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(corresponds to instant formula III),
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(corresponds to instant formula VIII), and
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(corresponds to instant formula XX).
In instant formula III, the three rings fused together are (from left to right):
Triazole, piperazine, and 1,4-dihydropyridin-4-one
In instant formula VIII, the three rings fused together are (from left to right):
Phenyl, piperidine, and 1,4-dihydropyridin-4-one
In instant formula XX, the three rings fused together are (from left to right):
Pyridine, cyclohexane, and 1, 2-dihydropyridine-2-one
Clearly no ‘‘single structural similarity’’ can be seen amongst the different core structures described above which are fused ring systems made up of rings of different electronic (and, therefore, chemical) properties.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. § 134 and 37 CFR41.31 (a) (1) (emphasis provided).
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1, 7, 8, and 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
In the instant case, claim 1 is directed to a compound of the following structure:
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(wherein the variables are defined in instant claim 1)
and claims 7, 8, and 22 are encompassed by claim 1. According to the instant specification (para. 0001), these compounds are useful as hepatoselective Polyadenylating Polymerases 5 and 7 (PAPD 5 and 7).
As stated above in the “Claim Rejections – Improper Markush Grouping” section, instant formula (I) encompasses compounds possessing substantially different core structures that are substituted with different substituents. However, the specification only provides eight working examples, all of which are confined to a narrow subgenus sharing a single core scaffold and closely related substituents. The examples from the instant specification are reproduced below:
Ex. no.
Structure
Ex. no.
Structure
1
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5
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2
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6
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3
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7
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4
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8
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Note: Instant examples 1-4 and 6-8 are homologs.
The specification does not provide representative species spanning the full breadth of the claimed genus.
The prior art (Panarese et al.; WO 2020/106816 A1; published May 28, 2020) has disclosed compounds with the following core structure:
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that are used to inhibit the protein(s) encoded by hepatitis B virus (see Panarese, pg. 3, lines 13-20), but never explicitly state that those compounds are specifically useful in inhibiting PAPD5 and PAPD7. Note: proteins encoded by hepatitis B virus are different than PAPD5 and PAPD7 which are polymerases from the host cell, not virus (see abstract of Mueller, H. et al. Hepatology 2019, 69, 1398-1411.). Therefore, a compound with the core structure disclosed by Panarese also being able to inhibit PAPD5 and PAPD7 is unpredictable.
Thus, the instant specification does not provide sufficient support to demonstrate that all compounds of instant claim 1, including those possessing core structures such as the one disclosed in Panarese (see above) would exhibit PAPD5/7 inhibitory activity.
Accordingly, the specification does not demonstrate that the inventors were in possession of the full scope of the claimed genus of the compounds having PAPD5/7 inhibitory activity. The limited disclosure of a narrow subset of compounds, without representative species or structural guidance that correlates compound structure with PAPD5/7 inhibition, is insufficient to support the breadth of the claims.
Claims 7, 8, and 22, which are dependent on claim 1, are also rejected for further requiring and/or reciting limitations that do not have written description support.
Scope of Enablement
Claims 1, 7, 8, 21 and 22 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:
A compound having the following formula:
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wherein:
X3 = CH2R
R =
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or
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R1a = R1b = R1c = R1d = H
n1 = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16
n2 = 2, 3, 4, 5, 6, 7, or 8
n3 = 1, 2, 3, 4, 5, 6, 7, or 8
the sum of n2 and n3 does not exceed 14
R8 = H and C1-6 alkyl
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed to make and use the invention based on the content of the disclosure, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims hepatoselective inhibitors of PAPD 5 and 7 having a disease-modifying action in the treatment of diseases associated with PAPD 5 and 7 that include disease such as hepatitis B and liver cancer. Compositions comprising same; and methods of making and using same are also described in the instant specification.
State of the prior art and the predictability or lack thereof in the art
The prior art (Panarese et al.; WO 2020/106816 A1; published May 28, 2020) has disclosed compounds with the following core structure:
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that are used to inhibit the protein(s) encoded by hepatitis B virus (see Panarese, pg. 3, lines 13-20), but never explicitly state that those compounds are specifically useful in inhibiting PAPD5 and PAPD7. Note: proteins encoded by hepatitis B virus are different than PAPD5 and PAPD7 which are polymerases from the host cell, not virus (see abstract of Mueller, H. et al. Hepatology 2019, 69, 1398-1411.). Therefore, a compound with the core structure disclosed by Panarese also being able to inhibit PAPD5 and PAPD7 is unpredictable.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples
The specification only provides eight working examples, all of which are confined to a narrow subgenus sharing a single core scaffold and closely related substituents. The examples from the instant specification are reproduced below:
Ex. no.
Structure
Ex. no.
Structure
1
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3
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7
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4
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8
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Note: Instant examples 1-4 and 6-8 are homologs.
The breadth of the claims
The claims are broad insofar as the instant claims recite a compound of instant formula I wherein the compound can possess a structurally diverse range of chemical substituents and substantially different core scaffolds.
The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure
As stated above, the instant specification only provides a limited number of working examples, all of which are confined to a narrow subgenus sharing a single core scaffold and closely related substituents. The disclosure does not provide guidance or direction regarding how variations in core scaffold or substituent identity affect PAPD5 or PAPD7 inhibitory activity.
Furthermore, the prior art demonstrates that certain core scaffolds encompassed by the instant claims have not been explicitly shown to exhibit PAPD5 or PAPD7 inhibitor activity. Thus, such activity cannot be assumed for all members of the claimed genus. Accordingly, a POSITA would not be able to predict which combinations of core structures and substituents would result in PAPD5 or PAPD7 inhibition.
In view of the limited disclosure and the absence of guidance correlating structure with PAPD5 and PAPD7 inhibitory activity, a POSITA would require undue experimentation (i.e., in the form of engaging in extensive screening and experimentation across a large number of possible compounds) to identify compounds that exhibit PAPD5 and PAPD7 inhibitor activity.
Claims 7, 8, and 22, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
Regarding the limitation “prodrugs and complexes thereof” encompassed by instant claims 1, 7, 8, 21, and 22:
The quantity of experimentation needed to make or use the invention must be considered to determine if undue experimentation is present. With regard to quantity of experimentation needed, (note Wolff et. al., "Burger's Medicinal Chemistry and Drug Discovery," 5th Ed. Part 1, pp. 975-977 (1995) provided with this action), which emphasizes the many experimental factors for consideration for a successful prodrug as well as the difficulty in extrapolating data from one species to another. See p.975-977. “Extensive development must be undertaken to find the correct chemical modification for a specific drug. Additionally, once a prodrug is formed, it is a new drug entity and therefore requires extensive and costly studies to determine safety and efficacy.” Banker, et. al., (1996), Modern Pharmaceutics, p.596, section “B. Prodrugs”, last paragraph. In view of all these factors undue experimentation would be required to practice the invention.
The scope of prodrugs is not adequately enabled or defined. Applicants provide no guidance as how the compounds are made more active in vivo. The choice of a prodrug will vary from drug to drug. Therefore, more than minimal routine experimentation would be required to determine which ester will be suitable for the instant invention. The application does not provide any guidance for one skilled in the art on how the prodrug is converted to active compounds, by what mechanisms and at what site the prodrug will be activated, what in vivo enzymes are likely involved in cleaving the protected group, etc.
Applicants provide no reasonable assurance that any and all known prodrugs will have the ability to regenerate in vivo to the instant compounds by one or more biological processes. It is not the norm that one can predict with any degree of accuracy a particular prodrug form of an active compound will be more soluble, more easily handled in formulations or more bioavailable without actual testing in vivo. Pursuant to In re Wands, 8 USPQ2d 1400, factors such as direction or guidance are not seen in the specification.
Many functional groups (e.g., hydroxy, amino groups) present in drugs are capable at least in theory to being derivatized but determining what is a prodrug and what is not requires knowledge of an intended effect (i.e. modification of an undesirable property in the parent drug- poor solubility, poor bioavailability, poor shelf-life) which is never identified by the specification.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7, 8, 21, and 22 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.
Claims 1, 7, 8, and 21 recite “prodrugs and complexes thereof”. The term “prodrugs” and “complexes” render claims 1, 7, 8, and 21 indefinite as “prodrugs” and “complexes” do not have a defined structure known in the art. For example, one would not be apprised of the pharmacologically inactive form of the claimed compound from the simple recitation of “prodrug” as the compound itself has multiple sites to which a prodrug moiety could bind. Moreover, one could not ascertain as to which prodrug moieties are within the scope of the claim, resulting in millions of combinations of prodrug moieties associated with the claimed compound at different locations on its structure. One could not possibly envisage all the possibilities of a prodrug of any compound of the instant invention. Likewise, a person of ordinary skill in the art would not be able to predict all possible structural forms of complexes based solely on the structure of the parent compound.
Claim 22 is also rendered indefinite for further requiring and/or reciting the limitation of “prodrugs and complexes thereof” of claim 1.
Claim 1 recites, “X3 is selected from the group consisting of…
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…” However, X7 is not defined by claim 1. Thus, claim 1 is further rendered indefinite.
Claim 1 recites “optionally substituted” without specifying what substituents are encompassed. Neither the claim nor the specification discloses the types of substituents encompassed, the permissible number of substituents, or the positions at which substitution may occur. Therefore, it is unclear what chemical structures are encompassed by the term “optionally substituted” as the term could include an unlimited range of functional groups and substitution patterns, including those that would significantly alter the chemical and physical properties of the claimed compound. As such, a POSITA would not be able to determine the metes and bounds of the claimed invention with reasonable certainty and claim 1 is rendered indefinite.
Claims 7, 8, and 21 recite the limitation "isotopic isomers.” Claims 7, 8, and 21 are dependent on claim 1, however, claim 1 does not mention “isotopic isomers.” Thus, there is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 22 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.
Instant claim 22 is directed towards a composition comprising at least one compound according to claim 1 with no additional components specified. The claim language of instant claim 22 suggests that the composition can be made up of 100% of the compound of claim 1. Therefore, claim 22 is not further limiting the subject matter of the claim upon which it depends.
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.
Note on 35 USC § 102 and § 103 Rejections
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.
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.
(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, 7, 8, and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Han et al. (Han) (US 2015/0210682 A1; published July 30, 2015).
Han teaches dihydroquinolizinones for the treatment and prophylaxis of hepatitis B virus infection. One of these dihydroquinolizinones disclosed is the following:
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Example 218 of Han (pg. 177) is a compound of instant formula I wherein:
R8 = H
X6 = CR7 (R7 = H)
X5 = N
X2 = C
X4 = CHR5 (R5 = H)
R6 = C4 branched alkyl
Z1 = CR1 (R1 = H)
Z2 = CR4 (R4 = H)
X1 =
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R2 = C1 alkoxy
X3 = -OR
wherein R =
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193
263
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n1 = 3
R1a = R1b = H.
Instant claims 1, 7, 8, and 22 encompass this compound and, thus, are anticipated by Han.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 7, 8, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over:
Han et al. (Han) (US 2015/0210682 A1; published July 30, 2015).
Han discloses the following compounds:
Note: Compounds (including the ones listed below) disclosed by Han were tested for their capacity to inhibit HBsAg (hepatitis B virus surface antigen). All 218 compounds disclosed by Han were tested in the HBsAg Assay (as described on pg. 178, para. 2121-2123) and found to have IC50 ranging from 0.0003 µM to 30 µM.
Structure with isopropyl group
IC50 (µM)
Corresponding structure with tert-butyl group
IC50 (µM)
Example 120 (pg. 110):
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317
638
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0.002
Example 202 (pg. 163):
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319
634
media_image23.png
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0.002
Example 121 (pg. 112):
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253
513
media_image24.png
Greyscale
0.002
Example 203 (pg. 164):
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256
507
media_image25.png
Greyscale
0.0003
Example 122 (pg. 112):
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250
512
media_image26.png
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0.69
Example 204 (pg. 165, left col., structure before para. 2003):
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267
520
media_image27.png
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0.14
Example 123 (pg. 112):
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309
638
media_image28.png
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0.009
Example 131 (pg. 119):
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311
623
media_image29.png
Greyscale
0.001
Example 124 (pg. 114):
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240
519
media_image30.png
Greyscale
0.002
Example 132 (pg. 120):
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255
497
media_image31.png
Greyscale
0.001
Example 125 (pg. 114):
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247
506
media_image32.png
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3.15
Example 133 (pg. 121, left col., structure before para. 1626):
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259
497
media_image33.png
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0.33
Example 144 (pg. 131):
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508
955
media_image34.png
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0.026
Example 149 (pg. 133):
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381
716
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0.002
From the results summarized in the table above, Han demonstrates that compounds of near identical scaffolds that only vary in substitution between an isopropyl and tert-butyl group result in compounds that remain highly active, with IC50 values consistently within a low micromolar range (≤ 0.03 µM) when the compound is a racemate or when the compound is in its (S)-stereoisomeric form as shown below:
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512
735
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and
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642
742
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. Note that when the compound is in its (R)-stereoisomeric form, it is consistently less potent than when the compound is in its (S)-stereoisomeric form with IC50 greater than 0.1 µM (see examples 122, 125, 133, and 204 in table above).
While tert-butyl substituents may, in some instances, provide somewhat lower IC50 values (see example 123 vs. 131 and example 144 vs. 149, for instance), Han also shows that the isopropyl analogs overall retain strong inhibitory activity (i.e., having an IC50 being much lower than the maximum IC50 of 29 µM observed for example no. 85; see Table 1 on pg. 178 for IC50 of each compound) and at least in one instance (example 120 vs. 202) exhibit equivalent potency.
Han further discloses example 218 (pg. 177):
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426
861
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which is the tert-butyl counterpart of instant example 2 (disclosed in the instant specification; see pg. 88, para. 0327):
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202
419
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. Han does not disclose instant example 2. However, Han’s data establishes that variation between the isopropyl and tert-butyl substituents constitutes a result-effective variable that influences the compound’s HBsAg inhibitory activity.
Accordingly, it would have been obvious to one of ordinary skill in the art to:
replace the tert-butyl group in example 218 of Han with an isopropyl group
motivation to make this modification: As stated above, while tert-butyl substituents may, in some instances, provide somewhat lower IC50 values, Han also shows that the isopropyl analogs overall retain strong inhibitory activity and at least in one instance (example 120 vs. 202) exhibit equivalent potency
once the substitution is made as described in point (1) above, to specifically use the (S)-stereoisomeric form (i.e., instant example 2) is also obvious
motivation to use the (S)-stereoisomeric form: As stated above, when the compounds of Han are in its (R)-stereoisomeric form, it is consistently less potent than when the compound is in its (S)-stereoisomeric form with IC50 greater than 0.1 µM (see examples 122, 125, 133, and 204 in table above). Thus, a POSITA would be motivated to make and use instant example 2 instead of the (R)-stereoisomeric form of instant example 2.
Given the information provided by Han, such a substitution and selection of a stereoisomeric form represents routine optimization of a known compound.
Once instant example 2 is made by making the modifications to example 218 of Han as described above, it would have been obvious to make instant examples 1, 3, 4, and 6-8 as those compounds are all homologs.
According to MPEP 2144.09:
I. REJECTION BASED ON CLOSE STRUCTURAL SIMILARITY IS FOUNDED ON THE EXPECTATION THAT COMPOUNDS SIMILAR IN STRUCTURE WILL HAVE SIMILAR PROPERTIES
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c).
II. HOMOLOGY AND ISOMERISM ARE FACTS WHICH MUST BE CONSIDERED WITH ALL OTHER RELEVANT FACTS IN DETERMINING OBVIOUSNESS
Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) 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.).
Therefore, a POSITA would have been motivated to make homologs of instant example 2 (i.e., instant examples 1, 3, 4, and 6-8) as well since homologs are presumed to possess similar properties since due to their sufficiently close structural similarity.
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, 7, 8, 21, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1, 7, 8, 21, and 22 of U.S. Patent Application No. 18/869,126 (‘126).
The co-pending application (‘126) claims a method for treating disease due to infection with Hepatitis A Virus (HAV); or preventing HAV-related disease in a subject known or suspected to have been exposed to the virus; said method comprising administering to a subject in need thereof, an effective amount of a compound having formula (I):
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171
281
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Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof. It is noted here that formula (I) of ‘126 is the same as formula (I) of the instant application. The claimed method of ‘126 necessarily requires the use of a compound of instant formula (I) as an active agent. Thus, the compound of instant formula (I) is fully encompassed within the subject matter of the co-pending claims.
Accordingly, a POSITA would have found it obvious that the compound of instant formula (I) is not patentably distinct from the method of using that same compound (as disclosed in ‘126), since the method claims of ‘126 necessarily require possession and use of the identical compound.
Thus, the instant claims represent an obvious variation of the claims of the co-pending application as they are directed to the same compound that is already required to practice the claimed method of the co-pending application.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY H. MURRAY can be reached at (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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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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