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 .
Drawings
The drawings are objected to because figures 1-9 appear to have duplicates, or are insufficiently labeled. Figures 1-3, 4-5, 6-7, 8-9 appear to be duplicates of the same experimental conditions as described in the “Brief Description Of The Drawings” section in the specification. If Applicant intends for these figures to contain distinct data from one another, Applicant is required to update description of the figures in the specification. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Status of the Claims
Claims 1-19 are pending and examined.
Allowable Subject Matter
Claims 4-8 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 16-19 are allowed.
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, and 9-15 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 cocrystal comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and a coformer, wherein the conformer and specific ratio of upadacitinib:coformer is: 4-acetamidobenzoic acid at a ratio of 1:1, 4-hydroxybenzoic acid at a ratio of 1:1.5, 4-hydroxy-3-nitrobenzoic acid at a ratio of 1:2, 3,4-dihydroxybenzoic acid at a ratio of 1:1, or gallic acid at a ratio of 1:1, and wherein the aqueous solubility of the cocrystal is enhanced as compared to Upadacitinib as a freebase or salt.
(Of note: the examiner acknowledges that an increased aqueous solubility of cocrystals formed with 4-acetamidobenzoic acid, 4-hydroxybenzoic acid, 4-hydroxy-3-nitrobenzoic acid, 3,4-dihydroxybenzoic acid, or gallic acid, when compared to Upadacitinib as a free base or salt is shown.)
Does not reasonably provide enablement for:
A cocrystal comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and a coformer, wherein the coformer is any and all aryl carboxylic acids, any and all substituted benzoic acids, or any and all species from the structure of Formula (I). As shown in the instant Specification at paragraph 55, Examples of benzoic acids and substituted benzoic acids include but are not limited to the following compounds: 5-cyano-1,3-benzenedicarboxylic acid, mellophanic acid, and pyromellitic acid. Paragraph 55 includes a laundry list of distinct compounds. Moreover, the term “substituted” in the claims is broadly defined by the Specification at paragraph 36 as shown below.
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A Upadacitinib:Coformer ratio of outside of the specific values used in examples, as listed above.
A cocrystal having reduced aqueous solubility, reduced dissolution, enhanced bioavailability, enhanced stability, increased Cmax, increased or decreased Tmax, increased half-life, increased AUC, enhanced processability, and reduced hygroscopicity, relative to Compound 1 as a free base or a salt, including solvates, hydrates, and polymorphs of any thereof.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Shukla, R. (The origin of synthons and supramolecular motifs: beyond atoms and functional groups), IUCrJ, Vol. 12, pp. 334-357 (Year: 2025) explains that knowledge of hydrogen bonding alone cannot predict the formation of a cocrystal, and only experimental verification can verify successful cocrystal formation. (See page 12-13; Introduction).
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention: Claim 1 is drawn to a cocrystal comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and a coformer, wherein the coformer is an aryl carboxylic acid. Claim 2 is drawn to the cocrystal of claim 1, wherein the aryl carboxylic acid is a substituted benzoic acid. Claim 3 is drawn to the cocrystal of claim 2, wherein the substituted benzoic acid has a structure of Formula (I), wherein R1 is -NHC(O)CH3 or -OH; R2 is -H, -OH, or NO2; and R3 is -H, -OH, or NO2.
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Claim 9 is drawn to the cocrystal of claim 1, wherein a molar ratio of Compound 1(Upadacitinib) to coformer is from about 5:1 to about 1:5. Claim 10 is drawn to the cocrystal of claim 9, wherein the molar ratio is from about 2:1 to about 1:2, or from about 1:1.5 to about 1.5:1. Claim 11 is drawn to the cocrystal of claim 9, wherein the molar ratio is about 1:1. Claim 15 is drawn to the cocrystal of claim 1, having one or more of reduced aqueous solubility, reduced dissolution, enhanced bioavailability, enhanced stability, increased Cmax, increased or decreased Tmax, increased half-life, increased AUC, enhanced processability, and reduced hygroscopicity, relative to Compound 1 as a free base or a salt, including solvates, hydrates, and polymorphs of any thereof.
However, aryl carboxylic acid, substituted benzoic acid, and Formula (I) as claimed, are broad genera while the Applicant only teaches a select number of species within these genera ( 4-acetamidobenzoic acid, 4-hydroxybenzoic acid, 4-hydroxy-3-nitrobenzoic acid, 3,4-dihydroxybenzoic acid, and gallic acid.) Cocrystal formation is highly unpredictable, and demonstration of success using these select species does not enable one skilled in the art to practice the claimed invention using any and all species within these genera.
The Applicant only shows specific Upadacitinib:coformer ratios for each species shown through working example. Cocrystals are a highly unpredictable art, and demonstration of success using select ratios, does not enable one skilled in the art to practice the claimed invention using the broad range of ratios claimed.
Applicant has shown in the specification that the cocrystals in the examples have enhanced aqueous solubility relative to freebase Upadacitinib, yet claims reduced aqueous solubility, and has shown that the stability of the cocrystals is not significantly different than that of free base Upadacitinib, yet claims enhanced stability. No other data was provided regarding any other property of the cocrystals claimed, and what was provided is contradictory to what is claimed.
Breadth of the Claims: The claims are broad in that the claims recite a cocrystal comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and a coformer, wherein the coformer is any and all aryl carboxylic acids, any and all substituted benzoic acids, or any and all species from the structure of Formula (I). The claims also recite broad ranges of upadacitinib:coformer ratios outside of what the Applicant has shown by working example, as well as pharmaceutical properties of the coformer that are either directly contradicted by the Applicant’s disclosure, or not supported in the specification at all.
However, cocrystal formation is highly unpredictable, as are the specific ratios at which they form, as well as the pharmaceutical properties they have. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the Specification and Existence of Working Examples: The specification describes utilizing a select few species of compounds (4-acetamidobenzoic acid, 4-hydroxybenzoic acid, 4-hydroxy-3-nitrobenzoic acid, 3,4-dihydroxybenzoic acid, and gallic acid) in formation of cocrystals with Upadacitinib, (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. The specification also shows specific ratios of upadacitinib:coformer at which these coformers form cocrystals with Upadacitinib, as well as enhanced aqueous solubility, and insignificant change in stability when compared to free base Upadacitinib.
However, demonstration of success using the select species shown by example does not enable one skilled in the art to practice the claimed invention using any and all aryl carboxylic acids, any and all substituted benzoic acids, or any and all species from the structure of Formula (I).
Additionally, the specific ratios of Upadacitinib:coformer, as well pharmaceutical properties that were shown by example, does not enable one skilled in the art to practice the claimed invention to the extent that the ratio of Upadacitinib:coformer, and pharmaceutical properties of each cocrystal are broader than exemplified.
While it is noted that the applicant has shown data for cocrystal formation in select species, at specific ratios of Upadacitinib:coformer, as well as enhanced aqueous solubility, the applicant is not enabled for a cocrystal comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and a coformer, wherein the coformer is any and all aryl carboxylic acids, any and all substituted benzoic acids, or any and all species from the structure of Formula (I), wherein Upadacitinib:coformer ratios and pharmaceutical properties are beyond what was directly exemplified.
Predictability and State of the Art: The state of the art at the time the invention was made was unpredictable and underdeveloped. It is known in the art that the development of cocrystals is highly dependent on the unique molecular properties between the coformer and the pharmaceutical compound. In addition, not all species of coformers are effective in forming cocrystals with all pharmaceutical compounds. While the formation of select cocrystals are exemplified by the applicant, due to the unpredictable nature of cocrystal formation the applicant does not disclose a cocrystal comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and a coformer, wherein the coformer is any and all aryl carboxylic acids, any and all substituted benzoic acids, or any and all species from the structure of Formula (I), wherein the Upadacitinib:coformer ratio is beyond the specific values for each specific cocrystal as exemplified, and wherein the pharmaceutical property of the cocrystal is anything beyond having enhanced aqueous solubility, as exemplified.
As previously mentioned, Shukla, R. (The origin of synthons and supramolecular motifs: beyond atoms and functional groups), IUCrJ, Vol. 12, pp. 334-357 (Year: 2025) explains that knowledge of hydrogen bonding alone cannot predict the formation of a cocrystal, and only experimental verification can verify successful cocrystal formation. (See page 12-13; Introduction).
Amount of Experimentation Necessary: The quantity of experimentation necessary to carry out the claimed invention is high, as the skilled artisan could not rely on the prior art or instant specification to teach a cocrystal comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and a coformer, wherein the coformer is any and all aryl carboxylic acids, any and all substituted benzoic acids, or any and all species from the structure of Formula (I), wherein Upadacitinib:coformer ratios or the range of pharmaceutical properties are beyond the aforementioned exemplifications.
In order to carry out the claimed invention, one of ordinary skill in the art would have to conduct XRPD experiments similar to the Applicant’s, with each and every species within the aryl carboxylic acid and substituted benzoic acid genera, and all species from the structure of Formula (I), showing the full breadth of Upadacitinib:coformer ratios used for each cocrystal formed, as well as directly test each cocrystal’s pharmaceutical properties as claimed.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1-3, and 9-15 are not considered to be fully enabled by the instant specification.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OROD MOTEVALLI whose telephone number is (571)272-6026. The examiner can normally be reached Monday - Friday 7:30AM - 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/OROD MOTEVALLI/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628