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 .
Election/Restrictions
Applicant's election with traverse of Group I, drawn to a compound of formula I, a pharmaceutical composition comprising the compound, a device comprising the pharmaceutical composition, or a combination of the compound with one or more active ingredients; and the following species:
the compound of Example 1 that is a single enantiomer compound: (R)-2-fluoro-4-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)benzonitrile as the elected compound species of formula I;
lactose as the elected species of carrier/excipient in the pharmaceutical composition;
a dry powder inhaler as the elected device; and
corticosteroid as the elected active ingredient in the combination
is maintained.
Claim 7 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on February 13, 2026.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species of compound of formula I conducted by the Examiner discovered a prior art by Blumenkopf et al. that renders obvious the claimed invention. Particularly, the prior art renders obvious the compound “5-(3-(methyl(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)amino)pyrrolidin-1-yl)picolinonitrile”, which has the structure of:
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.
However, it is noted that the prior art does not expressly teach the elected compound species, but renders obvious the elected species in view of the combination of the other prior references as set forth below. In light of this discovery, the search is additionally expanded to the subject matter of the compound of formula I to include “5-(3-(methyl(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)amino)pyrrolidin-1-yl)picolinonitrile” in addition to the elected compound species (i.e., Compound of Example 1), such that it does not encompass the full scope of the claims.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on July 21, 2026, wherein claims 1, 6 and 8-9 are canceled; claims 2-4 and 7 are amended; and claims 10-12 are newly added.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 2-5, 7 and 10-12 are pending.
Claim 7 remain withdrawn.
Claims 2-5 and 10-12 are under examination in accordance with the elected species along with the expanded compound species set forth in the Expansion of Election of Species Requirement above.
Priority
The instant application 18/282,068 filed on September 14, 2023 is a 371 of PCT/EP2022/056552 filed on March 14, 2022, which claims priority to, and the benefits of Foreign Application No.
EP21162525.6 filed on March 15, 2021.
Action Summary
Applicant’s amendment to the claims filed on July 221, 2026 have overcome each and every objection previously set forth in the Non-Final Office Action mailed on March 23, 2026.
Claims 8-9 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 are withdrawn in view of the claim amendments. These claims were cancelled.
Claims 1 and 8-9 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 are withdrawn in view of the claim amendments. These claims were cancelled.
Claims 1-5 and 8-9 rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives are withdrawn in view of the claim amendments; However, upon further consideration, the rejection has been reapplied in view of the claim amendments.
Claim 1 rejected under 35 U.S.C. 102(a)(1) as being anticipated by CAS Registry Number 2248077-03-2 (Entered STN Registry on November 13, 2018; cited in the previous Office Action mailed on December 15, 2025) are withdrawn in view of the claim amendments. The claim was cancelled.
Claims 1-5 and 8-9 rejected under 35 U.S.C. 103 as being unpatentable over Blumenkopf et al. (WO 02/00661 A1), as evidenced by CAS Registry Number 384336-88-3 (Entered STN Registry on January 19, 2002) are withdrawn in view of the claim amendments; However, upon further consideration, the rejection has been reapplied in view of the claim amendments.
Claim Interpretation
The claimed term “(R)-2-fluoro-4-(3-(methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl) amino) pyrrolidin-1-yl) benzonitrile”, when reasonably construed in light of page 15 of the specification, is a compound having the structure of:
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The claimed phrase “suitable to be administered by inhalation, selected from an inhalable powder, a propellant-containing metering aerosol or a propellant-free inhalable formulation” in claim 4 is reasonably construed to be an intended use of the pharmaceutical composition. Since the claim is interpretated to be a product, the intended use of the pharmaceutical composition does not further limit the structural components; and therefore, if the prior art(s) meet the structural limitation of the claimed product, it is capable of performing the intended use.
Claim Rejections - 35 USC § 112
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 2-5 and 10-12 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 (newly applied as necessitated by amendments).
Regarding claim 2, the newly added limitation “or a single enantiomer of said compound, a single diastereoisomer of said compound, a mixture of enantiomers of said compound, or a mixture of enantiomers of said compound; or a pharmaceutically acceptable salt or solvate of said compound, enantiomer, diastereoisomer, or mixture thereof” renders the claim indefinite, because it can leads to numerous interpretations and it is not clear which interpretations applies. The claim language uses multiple “or” coordinators in a single sentence that creates grammatical ambiguity, and it is hard to distinguish which limitation is supposed to be group together. For instance, it is not clear what is referring referred to as the “enantiomer, diastereoisomer, or mixture thereof “ in the phrase of “or a pharmaceutically acceptable salt or solvate of said compound, enantiomer, diastereoisomer, or mixture thereof”, because said phrase can be interpreted such that the compound is (a) (a pharmaceutically acceptable salt or a solvate of said compound) or (enantiomer, diastereoisomer, or mixture of said compound); or (b) the compound is (a pharmaceutically acceptable salt or a solvate of said compound) or (enantiomer, diastereoisomer, or mixture of the pharmaceutically acceptable salt or a solvate of said compound). Additionally, the phrase “a mixture of enantiomers of said compound” is repeated twice in the claim, and it is also not clear if the second recitation of “a mixture of enantiomers of said compound” is referring to a different mixture of enantiomers recited before. If so, it is not clear what is the difference between each recited mixture. Accordingly, claims 3-5, 10-12 are rejected based on their dependency on a rejected base claim.
Regarding claim 10-12, the recitation of “enantiomer, diastereoisomer or mixture thereof, or pharmaceutically acceptable salt or solvate thereof” in the preamble renders the claim indefinite, because it is not clear if the “enantiomer” recites therein is referring to (a) the “single enantiomer of said compound”; or (b) the “enantiomer” recites in the phrase of “a pharmaceutically acceptable salt or solvate of said compound, enantiomer, diastereoisomer, or mixture thereof”. It is also not clear if the “diastereoisomer” refers therein is referring to the (a) the “single diastereoisomer of said compound”; or (b) the “diastereoisomer” recites in the phrase of “a pharmaceutically acceptable salt or solvate of said compound, enantiomer, diastereoisomer, or mixture thereof”. It is also not clear of the “mixture thereof” is referring to (a) “a mixture of enantiomers of said compound”; or the “mixture” recites in the phrase of “a pharmaceutically acceptable salt or solvate of said compound, enantiomer, diastereoisomer, or mixture thereof”. Since the recitation in the preamble can be interpreted in various ways, the metes and bounds of the compound are indefinite as one of ordinary skill in the art cannot reasonably determine which interpretations applies with reasonable certainty.
Claims 2-5 and 10-11 are rejected on the basis that it contains an improper Markush grouping of alternatives (newly reapplied as necessitated by amendments). 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). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 2 and 10-11 is improper because the alternatives defined by the Markush grouping do not share a substantial structure feature that has been shown to be essential to their asserted common utility. Although the specification generally attributes JAK inhibiting utility to the claimed compounds, the existence of an asserted common utility alone is insufficient where the members do not share a substantial structural feature essential to that utility.
In the present case, claim 2 recites 10 compound species specifically enumerated in example 1-10 of the specification; and claims 10 limits the claimed subject matter to 9 compound species, and claim 11 limits the claimed subject matter to 8 compound species.
The enumerated compounds encompass substantially different molecular architecture, including different ring systems, substitution patterns, and terminal functional domains; and the specification does not establish these structurally diverse species possess the asserted common utility by virtue of the shared N-pyrrolidine moiety.
Particularly, the Markush grouping includes a variety of compound species, such as (R)-6-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-N-(thiazol-2-yl )nicotinamide (i.e., the compound of Example 3 having the structure of:
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according to page 16 of the specification); ethyl 7-((1-(4-cyano-3-fluorophenyl)pyrrolidin-3-yl)amino)thieno[3,2-b]pyridine-6-carboxylate (i.e., the compound of Example 7 having the structure of:
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according to page 18 of the specification); and methyl 2-(4-chloro-2-fluorophenyl)-2-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)acetate (i.e., the compound of Example 5 having the structure of:
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according to page 17 of the specification). These compounds species do not share the that do not share a substantial structure feature in common.
It is respectfully noted that these compound species only share the N-pyrrolidine moiety (
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) in common, and that does not constitute a significant portion of the compound as a whole. According to Frazee et al. (WO 2007/065093 A2), compound represented by the formula I
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is a progesterone receptor modulator useful for treating a patient with endometriosis or uterine fibroids (see e.g., p. 1, line 3-4; abstract). Even though the compound taught by Frazee et al. share the same technical feature (
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), said compounds are taught to have progesterone receptor modulating activity rather than inhibiting JAK kinases. Therefore, it is not apparent that this common structure alone (
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) contributes to the substantial structure feature essential for the compound of formula I to give the desired property of inhibiting JAK kinases.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response to Arguments
Applicant's arguments filed on July 21, 2026 with respect to the rejection of claims 1-5 and 8-9 on the judicially-created basis that it contains an improper Markush grouping of alternatives have been fully considered but they are not persuasive.
Applicant canceled claims 1 and 8-9, amends claims 2-5, and newly added claims 10-12; therefore, the rejection of record has been revisited and modified in view of the claim amendments.
In Summary, applicant argues the claimed compounds all share “at least the structural similarity of a heterobicyclic moiety W linked via an amino-pyrrolidinyl group to a further specified substituted aryl or substituted heteroaryl moiety R2”; and a common utility of inhibiting kinase activity.
In response to applicant’s assertion that the claimed compound shares a substantial structure feature in common and a common utility that flows from the substantial structural feature, said assertion appears to be mere arguments without any factual support. Applicant does not provide any sound technical and scientific reasonings to support that the structurally distinct compounds encompassed by the Markush grouping, for example, “ethyl 7-((1-(4-cyano-3-fluorophenyl)pyrrolidin-3-yl)amino)thieno[3,2-b]pyridine-6-carboxylate” and “methyl 2-(4-chloro-2-fluorophenyl)-2-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)acetate” shown below:
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, in fact, shares a common substantial structure that has been shown to be essential to their asserted common utility of inhibiting kinase activity. As noted above, the only structure feature these claimed compounds all have in common is the presence of N-pyrrolidine moiety, and that moiety clearly does not constitute a significant portion of the compound as a whole. In other words, the structure they have in common does not occupy a large portion of their structures.
Soley to rebut applicant’s assertion that heterobicyclic moiety linked via an amino-pyrrolidinyl group to a further specified substituted aryl or substituted heteroaryl moiety is the substantial structure, Fu (WO 2004/099213) reports compound of Example 1:
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is a compound of formula I useful as antagonists of CRF1 receptors (see e.g., p. 29, line 1-5; p. 1, line 1-6). While said compound shares the N-pyrrolidine moiety, it does not share a common utility of inhibiting kinase activity. In addition, said compound contains a heterobicyclic moiety linked to the N-pyrrolidine moiety that is further substituted with a moiety containing phenyl, said compound is taught to have CFR1 receptor antagonizing effect rather than inhibiting kinase activity. Thus, the mere presence of N-pyrrolidine moiety in the compound does not give rise to the asserted common utility of inhibiting kinase activity.
Since Applicant fails to provide any objective evidence demonstrating that this N-pyrrolidine moiety alone constitutes a substantial structure feature essential for the compound to give the properties of inhibiting kinase activity. The mere fact that the claimed compound species all shared this N-pyrrolidine moiety
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 2-5 are rejected under 35 U.S.C. 103 as being unpatentable over Blumenkopf et al. (WO 02/00661 A1; cited in the previous Office Action), as evidenced by CAS Registry Number 384336-88-3 (Entered STN Registry on January 19, 2002; cited in the previous Office Action) (newly reapplied as necessitated by amendments).
Blumenkopf et al. teaches a compound of Example 171, 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-carbonitrile, is an exemplary compound of the formula I useful as inhibitor of protein kinases, such as the enzyme Janus Kinase 3 (see e.g., claim 21; p. 55, line 26-29; abstract). Please note the compound of Example 171 taught by Blumenkopf et al. is a compound having the structure of:
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, as evidenced by CAS Registry Number 384336-88-3. Blumenkopf et al. further teaches a compound of the formula
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, wherein R1 is a group of the formula
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; R5 is (C2-C9)heterocycloalkyl wherein the heterocyclcolakyl group must be substituted by one to three groups selected from, inter alia, (C1-C6)alkyl and a group of the formula (II)
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(see e.g., claims 1-2), wherein a is 0, 1, 2, 3, or 4; b, c, e, f are each independently 0 or 1; d is 0, 1, 2, or 3; R12 is (C6-C10)aryl or (C2-C9)heteroaryl, wherein the aryl or heteroaryl group is optionally substituted by one to four groups consisting of, inter alia, halo and cyano (see e.g., claim 20). Blumenkopf et al. further teaches the (C2-C9)Heterocycloalkyl refers to, inter alia, pyrrolidinyl or piperidinyl (see e.g., p. 6, line 31 to p. 7, line 5); (C6-C10)aryl refers to phenyl (see e.g., p. 7, line18); and (C2-C9)heteroaryl refers to, inter alia, pyridyl or pyrimidyl (see e.g., p. 7, line 6-17). Blumenkopf et al. further teaches a pharmaceutical composition comprising an amount of the compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier (see e.g., claim 22; page 11, line 29 to page 12, line 3). Blumenkopf et al. further teaches capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base (see e.g., p. 26, line 5-8). Blumenkopf et al. further teaches aerosol formulations for treatment of the conditions (e.g., asthma) in the average adult human are preferably arranged so that each metered dose or “puff” of aerosol contains 20 µg to 1000 µg of the compound of the invention; and administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each times (see e.g., p. 26, line1 4-19). Blumenkopf et al. further teaches the compound of formula (I) administered in a pharmaceutically acceptable form either alone or in combination with one or more additional agents which modulate a mammalian immune system or with anti-inflammatory agents, agents which may include but are not limited to anti-inflammatory steroids (e.g. prednisolone or dexamethasone); and such agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice (see e.g., p. 26, line 20-30).
The difference between the compound of Example 171 of Blumenkopf et al. and the expanded compound species, 5-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)picolinonitrile, is shown below (see shaded):
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.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to select compound 171 of Blumenknopf as a starting compound and prepare the closely related compound presently claimed by selecting, from the structural alternatives expressly taught by Blumenknopt for compounds of Formula I, a pyrrolidnyl heterocycloalkyl group in place of piperidinyl heterocycloalkyl group of Example 171, selecting the corresponding substitution pattern lacking the methyl substituent present on the heterocycloalkyl ring of Example 171, and selecting the claimed pyridyl arrangement of the heteroaryl moiety. The resulting compound retains the methyl-substituted pyrrolo[2,3-d]pyrimidiyl amino portion, saturated nitrogen-containing pyridyl moiety and cyano-substituted pyridyl of Example 171, while employing a a pyrrolidinyl heterocycle, the corresponding substitution pattern lacking the methyl substituent present on the piperidinyl ring of Example 171, and the claimed pyridyl nitrogen arrangement, each as encompassed by the structural alternatives disclosed by Blumenknopf for compounds of Formula I.
One would have been motivated to make these selections because Blumenknopf does not disclose Example 171 in isolation, but expressly identifies Example 171 as an exemplary compound falling within Formula I and useful as an inhibitor of protein kinases, including Janus Kinase 3, while further teaching within the same Formula I genus the structural alternatives corresponding to the difference between Example 171 and the claimed compound. In particular, Blumenknopf teaches that the relevant heterocycloalkyl group may be, inter alia, pyrrolidinyl or piperidinyl (see e.g. p 6, l. 31-p.7, l. 5), teaches the permitted substitution of that heterocycloalkyl group by groups including C1-C6 alkyl and the Formula II substituent, and identifies pyridyl as a contemplated heteraryl group (see e.g., p. 7, ii, 6-17). Thus, the proposed modifications represent selection among structural alternatives that Blumenknopf itself teaches for members of the same Formula I, rather than structural modifications derived from Applicant’s disclosure.
One of ordinary skill in the art would have had a reasonable expectation of success in obtaining a compound retaining the protein-kinase inhibitory activity taught by Blumenknopf because the resulting compound would remain within Formula I class expressly disclosed by Blumenknopf and would preserve the substantial structural feature of the exemplified kinase inhibitor of Example 171. Blumenknopf expressly presents the foregoing heterocycloalkyl as permissible structural variations within the same class of compounds and identifies Formula I compounds, including Example 171, as useful protein-kinase inhibitors. Accordingly, one of ordinary skill in the art would have reasonably expected a closely structurally related Formula I analog obtained through Blumenknopf’s expressly taught structural alternatives to retain the disclosed protein-kinase inhibitory utility.
Regarding the limitation of “[a] pharmaceutical composition comprising the compound…in admixture with one or more pharmaceutically acceptable carriers or excipients” in claim 3, and “[t]he pharmaceutical composition… suitable to be administered by inhalation, selected from an inhalable powder” in claim 4, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the pharmaceutical composition comprising the modified compound set forth above with a pharmaceutical acceptable carrier. One would have been motivated to do so, because Blumenkopf et al. teaches a pharmaceutical composition comprising an amount of the compound of formula I and a pharmaceutical acceptable carrier. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound set forth above in admixture with a pharmaceutical acceptable carrier would have successfully arrive at a pharmaceutical composition; and that renders obvious the limitation of “suitable to be administered by inhalation, selected from an inhalable powder” by meeting the structural limitation of the pharmaceutical composition.
Regarding the limitation of “[a] device comprising the pharmaceutical composition… selected from the group consisting of single- or multi-dose dry powder inhaler” in claim 5, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at a single- or multi-dose dry powder inhaler comprising the pharmaceutical composition set forth above. One would have been motivated to do so, because Blumenkopf et al. teaches capsules and cartridges for use in an inhaler may be formulated containing a powder mix of the compound of formula I and a suitable powder base, and the aerosol formulations may administer several times daily giving 1, 2 or 3 doses each time. Therefore, Blumenkopf et al. itself would have suggested a dry powder inhaler suitable for delivering a single or multi-dose. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the pharmaceutical composition set forth above can be formulated into a powder mix used in an inhaler that delivers a single or multiple doses each time, and said inhaler renders obvious the limitation instantly claimed. Please note the powder mix in an inhaler is a dry powder.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on July 21, 2026 with respect to the rejection of claims 1-5 and 8-9 rejected under 35 U.S.C. 103 as being unpatentable over Blumenkopf et al. (WO 02/00661 A1), as evidenced by CAS Registry Number 384336-88-3 (Entered STN Registry on January 19, 2002) have been fully considered but they are not persuasive.
Applicant canceled claims 1 and 8-9, and newly added claims 10-12; therefore, the rejection of record has been revisited and modified in view of the claim amendments.
In Summary, applicant argues the rejection of record is based on impermissible hindsight reasons because it lacks lead compound analysis in determining obviousness, and there is no explanation as to why one of ordinary skill in the art would have had selected the compound of Example 171 of Blumenkopf et al. among 324 compound species for modification.
In response to applicant’s argument that there is no motivation to select compound of Example 171 of Blumenkopf et al. among the 324 compounds disclosed therein, said argument is not found persuasive. According to MPEP 2141.02, VI, “‘the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…’ In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also MPEP § 2123”. Same logic is applicable to instant product claim(s), the mere fact that Blumenkopf et al. teaches other exemplary compound species of formula I does not constitute a teaching away from selecting the compound of Example 171, because Blumenkopf et al. itself does not criticize, discrete, or otherwise discourage the use of compound of Example 171 as the compound of formula I for inhibiting Janus Kinase 3. Instead, Blumenkopf et al. clearly exemplifies the compound of example 171 (see e.g., p. 53, line 26-29; p. 9, line 33 to p.11, line 28) and particularly claim that said compound can be selected as the compound of the formula in the preferred embodiment (see e.g., claim 21). Thus, one of ordinary skill in the art would have had the reason to select compound of example 171 as it is one of the preferred embodiments of the disclosure.
Therefore, the rejection of record has been maintained, but revisited and modified in view of the claim amendments for the reasons set forth herein.
Claims 2-5 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Su et al. (US 10,369,153 B2), in view of Blumenkopf et al. (WO 02/00661 A1; cited in the previous Office Action) and Flanagan et al. (J Med Chem, 2010. Vol. 53(24): 8468-8484) and Chough et al. (Bioorg Med Chem, 2018. Vol. 26(8): 1495-1510), as evidenced by CAS Registry Number 384336-88-3 (Entered STN Registry on January 19, 2002; cited in the previous Office Action).
Su et al. teaches a compound 105 having the structure of:
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is an exemplary compound of formula (I) that inhibited at least one kinase chosen from Janus kinase 1 (JAK1), JAK2, JAK3 and TYK2 (see e.g., Col. 73, line 50-65; Col. 4, line 33-37); and said compound 105 has an IC50 value of 0.0140 μM in the JAK1 kinase assay, an IC50 value of 0.0487 μM in the JAK2 kinase assay; and IC50 value of 0.3594 μM in the JAK3 kinase assay (see e.g., Col. 143, line 60-65; Col. 144, line 25-34). Su et al. further teaches a composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described therein and at least one pharmaceutically acceptable carrier (see e.g., Col. 4, line 29-32); and can be administered in various known manner, such as by inhiation spray (see e.g., Col. 19, line 53-61).
Su et al. does not teach the elected species of compound of formula (I). Su et al. also does not teach the device as claimed in claim 5.
Blumenkopf et al. teaches a compound of Example 171, 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-carbonitrile, is an exemplary compound of the formula I useful as inhibitor of protein kinases, such as the enzyme Janus Kinase 3 (see e.g., claim 21; p. 55, line 26-29; abstract). Please note the compound of Example 171 taught by Blumenkopf et al. is a compound having the structure of:
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234
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, as evidenced by CAS Registry Number 384336-88-3. Blumenkopf et al. further teaches a compound of the formula
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133
213
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, wherein R1 is a group of the formula
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123
168
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; R5 is (C2-C9)heterocycloalkyl wherein the heterocyclcolakyl group must be substituted by one to three groups selected from, inter alia, (C1-C6)alkyl and a group of the formula (II)
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201
590
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(see e.g., claims 1-2), wherein a is 0, 1, 2, 3, or 4; b, c, e, f are each independently 0 or 1; d is 0, 1, 2, or 3; R12 is (C6-C10)aryl or (C2-C9)heteroaryl, wherein the aryl or heteroaryl group is optionally substituted by one to four groups consisting of, inter alia, halo and cyano (see e.g., claim 20). Blumenkopf et al. further teaches the (C2-C9)Heterocycloalkyl refers to, inter alia, pyrrolidinyl or piperidinyl (see e.g., p. 6, line 31 to p. 7, line 5); (C6-C10)aryl refers to phenyl (see e.g., p. 7, line18); and (C2-C9)heteroaryl refers to, inter alia, pyridyl or pyrimidyl (see e.g., p. 7, line 6-17). Blumenkopf et al. further teaches capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base (see e.g., p. 26, line 5-8). Blumenkopf et al. further teaches aerosol formulations for treatment of the conditions (e.g., asthma) in the average adult human are preferably arranged so that each metered dose or “puff” of aerosol contains 20 µg to 1000 µg of the compound of the invention; and administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each times (see e.g., p. 26, line1 4-19).
Flanagan et al. teaches early structure-activity relationship (SAR) revealed that compounds possessing cyclic, lipophilic, amino headgroups provided the best JAK3 enzyme potency (e.g., 2a-i) as illustrated in Table 1 below:
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622
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. Flanagan et al. further teaches it was observed that compounds possessing an N-methyl-cycloalkyl headgroup motif exhibited an improvement in cell potency, and this was unexpected based solely on consideration of JAK3 potency, which remained approximately the same as compared with earlier compounds (e.g., 2a-c); However, the N-methyl-cycloalkyl analogues demonstrates greater potency against JAK1 (e.g., 2e-i), suggesting that the combination of JAK1 and JAK3 (or JAK1 alone) may be key to realizing the improved cellular potencies observed (see e.g., p. 8469, right column, “Results” section, 1st paragraph).
Chough et al. teaches the most important interaction of tofacitinib, a JAK3 inhibitor (see e.g., p. 477, right column, line 16), in its binding with JAKs appears to come from the pyridopyrimidine ring; and the next important interactions are 4 van der Waals interactions with four carbon atoms (C4-C7) at the piperidine ring illustrated as follows:
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; and envisioned that, to tune the inhibition selectively for JAK1 over JAK2, new structural motifs could be explored for the substituted aminopiperidine moiety (see e.g., p. 479, left column, “Strategy”, 1st paragraph). Chough et al. further teaches for the selection of a new scaffold, substituted piperidine and pyrrolidine scaffold at position A were screened as shown below:
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614
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; and reports that while compound 6c exhibited strong inhibition against JAK1, 6d displayed very low inhibition against JAK1; therefore, compound 6c was selected as the scaffold for further SAR studies for finding inhibitors with high JAK1/ JAK2 selectivity (see e.g., p. 479, right column, 1st paragraph).
In the present case, the difference between the Compound 105 of Su et al. and the claimed elected compound species is that the prior art compound has the pyrrolidine-N-methyl moiety attached to the pyridopyrimidine ring rather than the claimed N-methyl-pyrrolidine moiety shown below (see shaded):
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.
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to select the compound 105 of Su et al., and then modifying said compound by replacing the pyrrolidine-N-methyl moiety with the N-methyl-pyrrolidine moiety, thereby arriving at the claimed invention.
One would have been motivated to modify the compound 105 of Su et al. by selecting N-methyl-pyrrolidine in place of pyrrolidine-N-methyl in between the pyridopyrimidine ring and the substituted phenyl, because Su et al. expressly identifies compound of Example 105 as a compound of formula (I) useful for inhibiting at least one kinase selected from JAK1, JAK2 ang JAK3; Blumenkopf et al. expressly teaches compound of Example 171, which contains the N-methyl-piperidinyl moiety as the NR4-(C2-C9)heterocycloalkyl moiety, is an inhibitor of protein kinases, such as the enzyme Janus Kinase 3, and further teaches the (C2-C9)heterocycloalkyl may be pyrrolidinyl or piperidinyl. Thus, Blumenkopf et al. itself would have suggested pyrrolidinyl as an alternative to piperidinyl at R5 of its formula I while retaining the janus kinase inhibiting effect. Furthermore, Flanagan et al. expressly teaches compounds possessing an N-methyl-cycloalkyl headgroup motif exhibited greater potency against JAK1 while retaining their JAK3 potency; and Chough et al. demonstrates pyrrolidine-NH- moiety and N-methyl-pyrrolidine moiety are both tolerated, including exemplifying compound 6d (with pyrrolidine-NH- moiety) and compound 6c (with N-methyl-pyrrolidine moiety). Accordingly, the prior arts would have suggested the incorporation of N-methyl-pyrrolidine as an alternative to link the pyridopyrimidine ring with the substituted phenyl while retaining the disclosed janus kinase inhibiting effect with the benefits of enhancing potency against JAK1.
One of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because Blumenkopf et al. exemplifies compound of Example 171 as an inhibitor of JAK3, which contains the N-methyl-piperidinyl moiety as the NR4-(C2-C9)heterocycloalkyl moiety, and suggested that piperidinyl and pyrrolidinyl are both tolerated as the (C2-C9)heterocycloalkyl group; therefore, the teachings of prior arts would have provided the skill artisan with a reasonable expectation that substituting the pyrrolidine-N-methyl moiety of Compound 105 of Su et al. with the N-methyl-pyrrolidine moiety taught by Blumenkopf et al. could likewise be successful in arrive new analogs while retaining the JAK kinase inhibiting effect.
Regarding the limitation of “[a] pharmaceutical composition comprising the compound…in admixture with one or more pharmaceutically acceptable carriers” in claim 3, and “[t]he pharmaceutical composition… suitable to be administered by inhalation, selected from an inhalable powder” in claim 4, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the pharmaceutical composition comprising the modified compound set forth above with a pharmaceutical acceptable carrier. One would have been motivated to do so, because Su et al. teaches the compound and at least one pharmaceutically acceptable carrier can be used to arrive at a composition that can be administered in various known manner, including inhiation spray (see e.g., Col. 19, line 53-61). Accordingly, Su et al. itself would have suggested that the pharmaceutical composition is suitable for inhalation. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound set forth above in admixture with a pharmaceutical acceptable carrier can successfully arrive at a pharmaceutical composition; and that renders obvious the limitation of “suitable to be administered by inhalation, selected from an inhalable powder” by meeting the structural limitation of the pharmaceutical composition.
Regarding the limitation of “[a] device comprising the pharmaceutical composition… selected from the group consisting of single- or multi-dose dry powder inhaler” in claim 5, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at a single- or multi-dose dry powder inhaler comprising the pharmaceutical composition set forth above. One would have been motivated to do so, because Blumenkopf et al. teaches capsules and cartridges for use in an inhaler may be formulated containing a powder mix of the compound of formula I and a suitable powder base, and the aerosol formulations may administer several times daily giving 1, 2 or 3 doses each time. Therefore, Blumenkopf et al. itself would have suggested a dry powder inhaler suitable for delivering a single or multi-dose. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the pharmaceutical composition set forth above can be formulated into a powder mix used in an inhaler that delivers a single or multiple doses each time, and said inhaler renders obvious the limitation instantly claimed. Please note the powder mix in an inhaler is a dry powder.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628
