Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Claims 1-10 are pending in the instant application.
Claims 1, 5, and 6 are amended.
Claims 2-4 and 8-10 are cancelled.
Claims 11-25 are new.
Claims 1, 5-7, and 11-25 are examined herein.
Priority
Acknowledgement is made of the applicant’s claim for foreign priority. It is noted, however, that applicant has not provided an English translation of the certified copy of Chinese Patent No. CN202010870701.6, filed on 26 August 2021; Chinese Patent No. CN202010869671.7, filed on 26 August 2021; Chinese Patent No. CN202110324874.2, filed on 26 March 2021; and Chinese Patent No. CN202110330670.X, filed on 26 March 2021; as required by 35 U.S.C. 119(b). The priority date of the instant application is 26 August 2021, the date of the PCT/CN2021/114756 application. Without the English translation, one cannot ascertain if the instant invention is present in the Chinese patent. Therefore, art prior to the PCT date, but not before the date of the Chinese application may be cited against the claims.
Information Disclosure Statement
The information disclosure statement (IDS), submitted on 24 February 2023 and 09 October 2025, are acknowledged and considered. The submissions are in compliance with the provisions of 37 CFR 1.97.
Response to Arguments
The amendment filed on 09 October 2025 has been entered.
In view of applicant amendment to claim 1 and cancellation of claim 4, the objection of record is withdrawn.
In view of applicant cancellation of claims 8-10, the 101 rejection of record is withdrawn.
In view of applicant cancellation of claims 8-10, the 112(a)-enablement rejection of record is withdrawn.
In view of applicant amendment to claims 1 and 5-6 and cancellation of claims 2-4 and 8-10, the 112(b) rejections of record are withdrawn.
In view of applicant amendment to claim 1, the 102(a)(1) rejection of record is withdrawn. Applicant has incorporated specific crystal forms and XRPD values that are not disclosed or suggested by Srinivasan (WO2019016828A1).
In view of applicant amendment to claim 1, the 103 rejections of record are withdrawn. Again, Applicant has incorporated specific crystal forms and XRPD values that are not disclosed or suggested by Srinivasan or Srinivasan in view of Csongor (US20060229297A1).
With respect to the double patenting rejection, Applicant requested the rejections be held in obeyance until patentable subject matter has been identified. However, the amended claims no longer recite the same subject matter as the co-pending application 18840634. The co-pending application specifically claims crystal from H of cariprazine embonate, the instant application claims crystal forms A, F, D, B, E, G, and I. Therefore the rejection is withdrawn.
In addition, new 112(a) and 112(b) rejections are necessitated by amendment (see below).
All rejections and objections not found below have been withdrawn.
REJECTIONS FACILITATED BY AMENDMENT
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 23-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while the prior art is enabled for the treatment of psychosis, bipolar disorder or acute mania, the art and specification fails to provide the required enablement for prevention of psychosis, bipolar disorder or acute mania. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The instant claims are drawn to the use of a pharmaceutically acceptable salt of cariprazine for treating and/or preventing psychosis, bipolar disorder, or acute mania. The specification fails to provide information that would allow the one skilled in the art to practice the prevention of psychosis, bipolar disorder, or acute mania.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is
permissible, if it is merely routine, or if the specification in question provides a reasonable
amount of guidance with respect to the direction in which the experimentation should
proceed to enable the determination of how to practice a desired embodiment of the
claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
the nature of the invention
the state of the prior art
the predictability of the art
the amount of direction or guidance provided
the presence or absence of working examples
the breadth of the claims
the quantity of experimentation necessary
the relative skill of those in the art
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention - is the use of a pharmaceutically acceptable salt for the treatment and/or prevention of psychosis, bipolar disorder, or acute mania.
The state of the prior art - the pharmacological art requires the screening of potential drug candidates in vitro and in vivo to determine if the drug candidates exhibit the desired pharmacological activities.
In order to treat a disease: one would need to precisely identify what the disease is, identify what biological target is connected with the disease, demonstrate that the drug candidate in some way modulates the normal processes of the biological target, and demonstrate that a patient benefited from such modification without detrimental side effects. Typically, this process includes in vitro laboratory screening, preclinical in vivo screening, and three phases of clinical trials. Once this arduous process has been successfully completed by a drug candidate, subsequent drug candidates will benefit from the established proof of concept. The subsequent drug candidates must demonstrate a substantial correlation between their biological activity and that of the known drug candidate.
In order to prevent a disease: one would need to precisely identify those subjects likely to acquire such a disease, administer Applicant’s claimed invention, and demonstrate that the patient did not develop the disease as a result of the administration of the claim invention.
In the instant case, the prior arts recognize that therapeutic agents have potential to treat psychosis, bipolar disorder, or acute mania. However, it is established in the prior art that these conditions are not therapeutically preventable. There are lifestyle changes that can be made to prevent the chance of developing psychosis (Cleveland Clinic. Psychosis. 2022) but not a therapeutic agent. For bipolar disorder and acute mania, there is no recognized therapeutic strategy for preventing the disease as a whole (Harvard Health Publishing. Bipolar Disorder. 2023). It is recognized that therapeutic treatment may prevent the frequent onset of manic symptoms.
The predictability or unpredictability of the art – the law recognizes the pharmaceutical art as an unpredictable art and requires each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970). Accordingly, the more unpredictable an area is the more specific disclosure is necessary in order to satisfy the statute. Section 2164.02 of the MPEP provides:
"[C]orrelation” as used herein refers to the relationship between in vitro and in
vivo animal model assays and a disclosed or a claimed method of use . . . if the
art is such that a particular model is recognized as correlating to a specific
condition, then it should be accepted as correlating unless the examiner has
evidence that the model does not correlate.
In light of these remarks, the Examiner finds that one of ordinary skill in the art would agree with the court; that is, the pharmaceutical art is unpredictable. Thus, a substantial correlation is necessary for establishing the potential of new therapeutics.
The amount of direction or guidance presented – the instant specification briefly provides an explanation of the biological activity of cariprazine on dopamine D3 receptor, dopamine D2 receptor and 5-hydroxytryptamine 2B receptor on page 1, and discusses cariprazine in the treatment of schizophrenia and bipolar disorder. There is no direction or guidance provided that supports the use of an antipsychotic as a drug for preventing psychosis, bipolar disorder, or acute mania.
The amount of guidance or direction to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. MPEP § 2164.03 (quoting In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970)). As identified supra, the pharmaceutical art is recognized as unpredictable.
Thus, in order to support a claim for preventing psychosis, bipolar disorder or acute mania a vast amount of evidence is required because such a claim is not supported by the prior art or the instant specification.
The presence or absence of working examples - there are no working or prophetic examples in the specification that demonstrate that the instant compounds or compositions thereof may prevent psychosis, bipolar disorder or acute mania. The assays in the specification supply the pharmacokinetic profile of various salts of cariprazine.
The breadth of the claims – is incommensurate in scope with the disclosure because a fair reading of the specification fails to support a finding that the pharmaceutically acceptable salts of cariprazine may prevent psychosis, bipolar disorder or acute mania in a patient.
The quantity of experimentation necessary – generally speaking, the amount of experimentation to transform a molecule into medicine is vast and the success thereof is low. Recent statistics indicate that the attrition rates during drug development remain high. Schafer et al. Drug Discovery Today 2008, 13 (21/22), 913-916. The article makes clear that there are many steps necessary to promote a new molecular entity toward its clinical use, any one of which is cumbersome.
For instance, Schafer et al. discloses: "proof of concept trials have failed when the decision to enter clinical development was based on preclinical experiments using the wrong compound, the wrong experimental model, or the wrong endpoint.” It can be gleaned from this article that a plethora of experimentation is needed to identify the lead compound (i.e. one among many in a Markush-type claim), to establish which preclinical tests are predictive of clinical success, and to establish which diseases are the best to target for each lead compound.
There is generally a vast amount of experimentation to take a drug from bench to the clinic. See e.g., Horig et al. Journal of Translational Medicine 2004, 2(44) (“Successful drug development requires satisfying a matrix of domains from relevance to the disease and the drug-ability of the target through feasibility and convenience of drug delivery, demonstration of favorable benefit-risk profile in order to achieve a drug label that reflects physician and patent acceptance.") The Examiner finds that one of ordinary skill in the art would agree with the statements in these articles; that is, the amount of experimentation required to enable a pharmaceutical drug is extensive.
The level of skill in the art - the level of ordinary skill in the art may be found by inquiring into: (1) the type of problems encountered in the art; (2) prior art solutions to those problems; (3) the rapidity with which innovations are made; (4) the sophistication of the technology; and (5) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of those factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983).
Based on the typical education level of the active workers in the field of pharmaceuticals and/or medicine, as well as the high degree of sophistication required to solve problems encountered in the art, the Examiner finds that a person of ordinary skill in the art would have at least a college degree in a field related to medicine and/or the pharmaceutical art and at least four years of work experience, i.e. a masters or doctorate level scientist/clinician.
Therefore, claims 23-25 are rejected because the Examiner finds that the Wands factors suggest a conclusion that the skilled artisan would not be able to make and use the instant invention without undue experimentation, although the level of skill for an ordinary person in the art is high. That is, due to the breadth of the claims, the unpredictability of the art, the lack of guidance or direction from the disclosure, the lack of any working examples, and the amount of experimentation needed illustrate that a person having ordinary skill in the art would not be able to prevent psychosis, bipolar disorder or acute mania.
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 6 and 19 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.
Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: addition of cariprazine embonate to an appropriate solvent or exposure to illumination to produce a crystal form as recited in claim 1. The steps as recited in claim 6 produce an amorphous form of cariprazine embonate, not a crystalline form.
The term “substantially” in claim 19 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Objections
Claims 20-22 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.
Allowable Subject Matter
Claims 1, 5, 7, and 11-18 are allowable over the prior art.
The closest prior art is Srinivasan et al. (WO2019016828A1). Srinivasan discloses the acid addition salt of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N',N'-dimethyl urea, also known as cariprazine. Srinivasan discloses organic acids including organic acids with greater than six carbons.
Srinivasan is silent on the embonate salt of cariprazine let alone the crystal forms of cariprazine embonate as recited in the instant invention. As Srinivasan does not disclose the crystal forms of cariprazine embonate the specific diffraction patterns as recited in claim 1 are also not taught. Obtaining a specific crystal form is considered unpredictable in the art. Srinivasan does not explicitly teach crystal forms A, F, D, B, E, G, and I nor does Srinivasan teach the method of preparation of embonate crystal forms A, F, D, B, E, G, and I found in the instant specification which would have guided the skilled artisan toward the crystal form. Therefore the embonate crystal forms A, F, D, B, E, G, and I are novel over the prior art.
Conclusion
Claims 1, 5, 7, and 11-18 are allowed.
Claims 6, 19, and 23-25 are rejected.
Claims 20-22 are objected to.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jerica K Wilson whose telephone number is (703)756-4690. The examiner can normally be reached Monday-Friday 9:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571)270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.K.W./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621