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 1-4, 9, 12-14, and 16-26 are pending. Claims 5-8, 10-11, and 15 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/EP2022/051786, filed on January 26, 2022. This application also claims the benefits of foreign priority to PCTEP2021051983, filed on January 28, 2021.
Specification - Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
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 1-4, 12-14, 18, 20, and 25 are objected to because of the following informalities:
Claim 4 should read:“A crystalline form of 1-{(R}-2-(2-Hydroxy-ethyl)-4-[2- trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl}-ethanone according to claim 1, characterized by peaks in an X-ray diffraction pattern at angles of refraction 2θ as depicted in Fig. 1.”
To avoid 112(b) issues and for consistency, claims 1-3, 12-14, 18, 20, 22, and 25 should read: “…characterized by a presence of peaks in an X-ray powder diffraction diagram at the following angles of refraction 2θ:” Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) - enablement
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 14 and 22-26 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention.
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, 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 a crystalline form of 1-{(R}-2-(2-Hydroxy-ethyl)-4-[2- trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl}-ethanone, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline form, pharmaceutical compositions prepared from such crystalline forms, and their use as CXACR3 receptor modulators in the treatment of various diseases and disorders related to the CXCR3 receptor and tis ligands.
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.
State of the prior art
Prior art referenced:
Caroff et al. (Caroff) (WO2016113344A1; published July 21, 2016) and
Furman (Furman, B. L. Current Protocols in Pharmacology 2015, 70, 5.47.1-5.47.20).
Caroff provides the earliest disclosure of the instant compound (herein, referred to as COMPOUND; see Caroff, pg. 50, example 35). Caroff also provides data on COMPOUND from various biological assays (i.e., in vitro experimentation). No in vivo results were provided by Caroff.
Furman describes “two protocols used to produce [streptozotocin] STZ-induced diabetes in mice (Basic Protocol 1) and rats (Basic Protocol 2). Basic Protocol 1 employs multiple administrations of low-dose STZ to produce diabetic mice, and is increasingly being used as an animal model for diabetes… Basic Protocol 2 is used to induce diabetes in rats with STZ… [Both of] these models are valuable for evaluating treatments for T1DM [i.e., type I diabetes mellitus] (pg. 5.47.1, 3rd paragraph and 1st sentence of 4th paragraph). In other words, animal models are important in evaluating treatments for disorders including type I diabetes.
The amount of direction or guidance present and quantity of experimentation necessary
The prior art does not disclose any results from animal studies that indicate COMPOUND (in its amorphous or crystalline form) can treat a disorder (which includes type I diabetes) in a subject. Additionally, in the absence of clear guidance, a person of ordinary skill in the art would require undue experimentation to determine which disorder (selected from (auto-) immune/ inflammatory mediated disorders, pulmonary disorders, cardiovascular disorders, infectious diseases, fibrotic disorders, neurodegenerative disorders, and tumor diseases) the crystalline form of COMPOUND (as disclosed in the instant case) can treat.
The presence or absence of working examples
The instant specification only provides working examples of three different forms of COMPOUND. There are no working examples of COMPOUND (in its crystalline form) treating any disorder selected from (auto-)immune/ inflammatory mediated disorders, pulmonary disorders, cardiovascular disorders, infectious diseases, fibrotic disorders, neurodegenerative disorders, and tumor diseases in a subject. Additionally, there are no working examples provided by the instant specification indicating that the crystalline form of COMPOUND can prevent any of the disorder types as listed above.
As such, “prevention” should be removed from instant claim 14.
The breadth of the claims
The claims are broad insofar as the instant claims recite a method for the prevention or treatment of disorders drawn from a wide and diverse set of disease categories including (auto-) immune/ inflammatory mediated disorders, pulmonary disorders, cardiovascular disorders, infectious diseases, fibrotic disorders, neurodegenerative disorders, and tumor diseases, wherein each disease category further encompasses numerous distinct diseases.
Claims 22-26, which are dependent on claim 14, are also rejected for further requiring and/or reciting non-enabling elements as described above.
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 and 12-14 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 and 12-14 recite the limitation "characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction”. There is insufficient antecedent basis for this limitation in the claim. As claims 1 and 12-14 are independent claims, they are the first claims to introduce characteristic peaks from an X-ray powder diffraction. Hence instead of stating “the presence of peaks in the X-ray powder diffraction diagram,” the claims should be rewritten to state the following:“characterized by a presence of peaks in an X-ray powder diffraction diagram at the following angles of refraction…”
Claim 14 recites “A method for the prevention or treatment of disorders… wherein the method comprises administering a crystalline form of 1-{(R}-2-(2-Hydroxy-ethyl)-4-[2- trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl}-ethanone.” The claim does not indicate the intended subject or entity to receive the administration of the crystalline compound, rendering the scope of claim 14 unclear.
Examiner interprets claim 14 to be a method for the prevention or treatment of disorders… wherein the method comprises administering a crystalline form of 1-{(R}-2-(2-Hydroxy-ethyl)-4-[2- trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl}-ethanone to a subject in need thereof (as stated in the instant specification, pg. 20, lines 4-9).
Claims 2-4, 9, 16-26 which ultimately depend on claims 1, 12, 13, or 14, are also rejected for further requiring and/or reciting the indefinite limitations of claims 1, 12, 13, or 14.
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 12,13, and 18-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by
Caroff et al. (Caroff) (WO2016113344A1; published July 21, 2016)
Caroff provides the earliest disclosure of the instant compound (herein, referred to as COMPOUND; see Caroff, pg. 50, example 35). Caroff reports that the crude form of COMPOUND was purified by Prep LC-MS (II) followed by Prep LC-MS (IV). Prep LC-MS (IV) requires two elution solvents: solvent A (which consists of water + 0.5% formic acid) and solvent B (which consists of MeCN) (pg. 32, lines 16-18). In other words, Caroff discloses a composition comprising COMPOUND dissolved in water and MeCN.
Note: water and MeCN are known to be excipients. See:
Baldrick, P. Regulatory Toxicology and Pharmacology 2000, 32, 210-218.; pg. 210, right col., middle of 1st paragraph, sentence starts with “Indeed, the 12 most common excipients…” and
Acetonitrile HP; Actylis.
https://www.safic-alcan.com/en/product-catalog/pharmaceuticals/actylis/acetonitrile-hp. (Last accessed October 24, 2025).
Caroff does not disclose the phase state (i.e., solid or liquid) of COMPOUND. It is noted here that, since Caroff does not disclose additional steps necessary to crystallize COMPOUND (as disclosed in the instant application), it is presumed that the purified COMPOUND disclosed in Caroff is non-crystalline. Regardless of the solid-state form of COMPOUND, once a crystalline polymorph is fully dissolved in a liquid carrier such as liquid excipients which include water and/or MeCN, the resulting solution no longer retains any crystalline structure and is indistinguishable from a solution prepared from COMPOUND in an amorphous form. Therefore, Caroff disclosing a composition comprising COMPOUND dissolved in water and MeCN reads on instant claims 12, 18, and 19. Since Caroff also teaches how to purify the crude form of COMPOUND using solvent A and B, Caroff is also disclosing a method of manufacturing a composition comprising COMPOUND dissolved in water and MeCN which reads on instant claims 13, 20, and 21.
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 12, 14, 18, 19, and 22-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-9, 11-21 of U.S. Patent Application No. 19109802 (‘802).
Although the claims at issue are not identical, they are not patentably distinct from each other because there is overlap between the instant claims and the claim set from the co-pending application.
Claims 1-9 of ‘802 are directed towards a pharmaceutical combination comprising:
the instant compound as the first active pharmaceutical ingredient (referred to as COMPOUND; note: the claim does not specify that COMPOUND has to be crystalline) and
an anti-CD3 monoclonal antibody as the second active pharmaceutical ingredient.
For embodiments in which COMPOUND is formulated for intravenous administration (as disclosed in claim 5), it is necessary for COMPOUND to be dissolved in a pharmaceutically acceptable excipient suitable for parenteral delivery such as MeCN or water as discussed above. Thus, the scope of claims 1-9 in ‘802 overlap with instant claims 12, 18, and 19 which recite a pharmaceutical composition comprising a crystalline form of COMPOUND and at least one pharmaceutically acceptable carrier. If the carrier used in the instant case is also a solvent suitable for intravenous administration and can dissolve the crystalline form of COMPOUND, then the resulting solution would be indistinguishable from a solution prepared from the non-crystalline form. Thus, under such conditions, the claimed pharmaceutical combination of claims 1-9 in ‘802 would not be patentably distinct from the pharmaceutical composition recited in instant claims 12, 18, and 19. Furthermore, even though the combination disclosed in ‘802 also includes a second active pharmaceutical ingredient, the open-ended term “comprises” in instant claims 12, 18, and 19 indicates that the composition disclosed in the instant case can also include other components such as an anti-CD3 monoclonal antibody as disclosed in ‘802.
Claim 17 of ‘802 is directed towards a pharmaceutical composition comprising COMPOUND and at least one therapeutically inert excipient. As stated previously, even though ‘802 does not specify whether COMPOUND is a crystalline or non-crystalline solid, if the inert excipient is a solvent that can dissolve crystalline COMPOUND, the resulting composition would be indistinguishable from a solution prepared from the non-crystalline form of COMPOUND. Under such conditions, claim 17 of ‘802 would not be patentably distinct from instant claims 12, 18, and 19.
Claim 11-16 and 18-21 of ‘802 are directed towards a method for the prevention and/or treatment of a disease (which includes type 1 diabetes) in a patient in need thereof, wherein the method comprises administering to the patient an effective amount of COMPOUND and an effective amount of an anti-CD3 monoclonal antibody. These claims encompass instant claims 14 and 22-26 which are directed towards a method for the prevention or treatment of disorders (which include type I diabetes), wherein the method comprises administering a crystalline form of COMPOUND. Although claims 11-16 and 18-21 of ‘802 do not explicitly require COMPOUND to be in crystalline form, their scope is sufficiently broad to include crystalline forms of COMPOUND. Likewise, although instant claims 14 and 22-26 do not explicitly require co-administration of an anti-CD3 monoclonal antibody, the open-ended transitional term “comprising” permits the inclusion of additional steps such as administering an effective amount of an anti-CD3 monoclonal antibody as recited in claims 11-16 and 18-21 of ‘802. Accordingly, the claimed methods are not patentably distinct.
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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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624