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 .
Status of Claims
Claims 1, 3-7, 34-35, 38-48 are pending.
Priority
Instant application 18/874,175 filed on 12/12/2024 claims priority as follows:
PNG
media_image1.png
121
746
media_image1.png
Greyscale
Information Disclosure Statement
All references from IDS(s) received 12/12/2024 have been considered unless marked with a strikethrough.
Drawings Objections
Figure 1 is objected to because the heading contains a typographical error: “XRPT” should read “XRPD”.
Figure 4 is objected to because the heading contains a typographical error: “TG/DTA thermogram fpr form A” should read “TG/DTA thermogram for form A”.
Figure 13 is objected to because the heading contains a typographical error: “XPRD patter of Form E” should read “XPRD pattern of Form E”.
Figure 13A is objected to because the heading contains a typographical error: “XRPD patterns of Form C material (top) anf Form E material (bottom)” should read “XRPD patterns of Form C material (top) and Form E material (bottom)”.
Specification Objections
Paragraph [0171] is objected to because it contains a typographical error: “Carious further aspects…” should read “Various further aspects…”
Claims Objections
Claims 3-7, and 35 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.
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 34 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 1 is indefinite because it does not present enough information to distinctly claim a crystalline form of compound 1. There is an overlap with the XRPD peak at 23.16 ± 0.2 (°2[Symbol font/0x71]), present in Forms B, C and E of the crystalline form of compound 1. Clarification of the claim language is required. With the claims as they stand, they do not distinctively claim ‘a crystalline form’, but based on evidence in the spec read on at least three different forms given the interpretation using the ‘or’ logic of the claim.
For example, the rejection would be withdrawn if claim 1 were amended to recite: A crystalline form of compound 1 characterized by an X-ray powder diffraction (XRPD) pattern comprising a peak at 8.33 and 23.16 ± 0.2 (°2[Symbol font/0x71]).
The term “associated with” in claim 34 is a relative term which renders the claim indefinite. The term “associated with” 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.
This relative term is not explicit as to its meaning; the association could be taken to be structural or functional; this makes the claim indefinite. Clarification of the claim language is required.
For example, the rejection would be withdrawn if claim 34 were amended to recite: “A method treating a condition associated with seizure, wherein the condition associated with seizure is epilepsy, generalized onset seizure or focal-onset seizure.
Claim Interpretation
Claim 48 is being interpreted as a product by process claim. See MPEP 2113 incorporated by reference herein.
Claim Rejections - 35 USC § 112 (a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement Rejection
Claims 38-48 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 method for preparing various crystalline forms of compound 1 employing specific solvents related to their individual preparations in the specification, does not reasonably provide enablement for a method for preparing a crystalline form of compound 1, using a generic first and/or generic second solvent. 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.
Breadth of the claims
The claims are broad and directed to a method of preparing a crystalline form of compound 1 using a first and second solvent.
Nature of the invention
The claims recite a method of preparing a crystalline form of compound 1 using a first solvent selected from esters, ethers, ketones, and nitriles (specification par. [0092]); and a second solvent selected from linear alkanes, cycloalkanes, petroleum fractions, and aromatic hydrocarbons (specification par. [0096]).
State of the prior art & Level of predictability in the art
Relevant prior art includes (Morissette et al. Advanced drug delivery reviews, 56, 2004, 275-300).
Morissette et al. describes how the fundamental mechanisms and molecular properties that drive crystal form diversity, specifically the nucleation of polymorphic forms, are not well understood (Introduction, p.276-77). Even in cases where the existence of a crystalline form is predicted, the stability relative to other crystalline packing arrangements has been difficult to estimate with accuracy (Introduction, col 1, p. 277).
Morissette et al. emphasizes how the importance of reliable preparation and preservation of the desired form of the drug substance must be demonstrated, and has become increasingly scrutinized by regulatory agencies as more sensitive and quantitative solid-state analytical methods have become available (Introduction, col 1, p. 277).
Additionally, Morissette et al. states that in order to fully control the crystallization process, the link between the physical or chemical process that influence nucleation and crystal growth needs to be better established (Introduction, col 2, p.277). Solvents, among other items, are a key hurdle faced in the development of combinatorial crystallization for small molecules. Small molecule crystallization employs a range of crystallization additives and processes. The additives include organic solvents with varying properties (e.g alcohols, acetone, hexane, ethyl acetate, etc.), water, acids, bases and co-crystal formers, as well as other compounds (e.g., small molecule templating agents, surfactants, pharmaceutical excipients, etc.) (Development, col 1, p. 281).
Finally, Morissette et al. describes that the value of composition of matter (CoM) patents on new chemical entities, including where appropriate, pharmaceutically acceptable salts, has been well appreciated. However, it is only within the last decade or so that the application of CoM patents has been significantly extended to cover all forms of the compound, including hydrates, solvates, co-crystals and polymorphs. Unlike salts, which for the most part can be prophetically claimed based on an understanding of the chemical structure of the compound and its ionization constants, the existence and identity of hydrates, solvates, co-crystals, and polymorphs have defied prediction. It is essential to prepare them, identify conditions for making them and evaluate their properties as valuable new pharmaceutical materials (Summary, col 2, p. 296).
Relevant prior art includes (Cruz-Cabeza et al. Communications Chemistry, 3, 142, 2020).
Cruz-Cabez et al. discloses how crystallization is the process by which molecular crystals are produced and the two steps involved, nucleation and growth. Nucleation and growth of different crystal structures (with identical composition and similar energies) under different crystallization conditions (solvent, composition, purity, temperature, pressure) can lead to a phenomenon known as crystal polymorphism (p. 1).
Kinetics and thermodynamics play a fine game in nucleation and crystal growth of various polymorphs (col 2, p.2). Gaining a better understanding of the kinetics of crystal nucleation and growth for a wide range of polymorphic systems is a must in order to establish better links between crystal forms and the conditions that afford them (col 1, p.3).
Relevant prior art includes (Brittain, H. G., ed. Polymorphism in pharmaceutical solids. CRC press, 2009).
Brittain discloses that one of the experimental variables that may influence the thermodynamic and kinetic control of solution crystallization is the variation of solvent identity. The relationship between solvent, nucleation and growth of a crystal is generally poorly defined, and may involve factors other than solvent identity, the selection of appropriate solvent descriptors remains a challenge (p. 148-149).
Relevant prior art also includes (Khoshkhoo et al. Journal of Physics D: Applied Physics, 26, 1993, B90-B93)
Khoshkhoo et al. discloses studies of the effect of solvent in crystallization of polymorphs using the drug sulphathiazole as a model compound. These recrystallization experiments reveal that not all of the known polymorphic forms can be crystallized from any given solvent by varying the supersaturation. Some solvents selectively favour the crystallization of a particular form or forms. It is considered that the solvent acts by selective adsorption to certain faces of some of the polymorphs, and thereby either inhibits their nucleation or retards their growth to the advantage of others (Abstract).
Level of one of ordinary skill
One of ordinary skill in the art would hold an advanced degree in organic synthesis and medicinal chemistry, as well as quantitative and qualitative analytical skills. Additionally, they would possess several years of professional experience.
Amount of direction provided by the inventor & Existence of working examples
In the experimental section, applicant has 1 method for preparing crystalline form of compound 1. The specific solvents used in that preparation were ethyl acetate and heptane.
Quantity of experimentation needed to make or use the invention based on the content of the disclosure
As shown above, in view of Morissette et al., which discloses that even in cases where the existence of a crystalline form is predicted, the stability relative to other crystalline packing arrangements has been difficult to estimate with accuracy.
In view of Cruz-Cabeza et al. that teaches how kinetics and thermodynamics play a fine game in nucleation and crystal growth of various polymorphs.
In view of Brittain which discloses that variation of solvent identity may influence the thermodynamic and kinetic control of solution crystallization.
Finally, further in view of Khoshkhoo et al. which discloses that recrystallization experiments reveal that not all of the known polymorphic forms can be crystallized from any given solvent by varying the supersaturation.
All of claim 38 is drawn to a method for preparing a crystalline form of compound 1. Based on the evidence above specific solvents lead to specific forms and without claiming specific solvents, one cannot determine if one skilled in the art would produce the claimed form. Further, given the unpredictability established above, such determination would be undue.
Based on the assessment and experimental methods discussed above, polymorph forms are unpredictable, claims 38-48 are rejected as failing to comply with the enablement requirement.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CINDY BAGNAL whose telephone number is (571)270-1080. The examiner can normally be reached M-F 8:00 am-4:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.B./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights