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 II, directed to a process for preparing a solid form or solid crystal form of N-methylisoindigo, in the reply filed on 09/21/2026 is acknowledged. The traversal is on the grounds that the Examiner’s assertion that the product as claimed can be made by another materially different process such as solvent evaporation does not establish distinctness as Claim 15 is not limited to cooling, addition of an antisolvent, or another particular precipitation mechanism. It broadly recites precipitating the claimed crystalline form from a solution comprising an organic solvent. The Requirement does not explain why solvent evaporation would fall outside that recited precipitation process or otherwise constitute a materially different process. Applicant further argues that the identified alternative does not establish that solvent evaporation would produce the product as claimed of a Crystal Form I having the recited X-ray powder diffraction characteristic, including the peak at about 7.71°. The Specification reports that different crystallization and recrystallization conditions produced different crystalline forms, that Samples 1-6 were different from Crystal Form I, and that Crystal Form I is unique in its properties and reproducible production and isolation (citing to U.S. Patent Application Publication No. 2025/0084035, paragraphs [0133], [0142], and [0148]).
This is not found persuasive because the Examiner has set forth that the product as claimed can be made by a materially process; the process claimed requires precipitating a crystalline form from a solution, while the Examiner proposes that the materially different solvent evaporation (removal of the solvent) can be used to prepare the crystalline form. From MPEP 806.05 (f) “Allegations of different processes or products need not be documented” and “If applicant convincingly traverses the requirement, the burden shifts to the examiner to document a viable alternative process or product, or withdraw the requirement”. Here, the Examiner has provided an example to support the determination that the inventions are distinct, and Applicant has not provided convincing evidence or arguments that the example suggested by the Examiner is not workable. The Examiner respectfully maintains the position that per MPEP 806.05(f), the burden has been met to show that the inventions are distinct because the product as claimed is shown to be made by a materially different process.
Further, Applicant appears to contend that different materials can be formed via different crystallization and recrystallization conditions falling within the scope of the instant claims. If this is the case, then the general process as claimed (“precipitating a crystalline form from a solution comprising an organic solvent”) can be used to make a materially different product, further satisfying the requirement of 806.05(f) “The inventions are distinct if… the process as claimed can be used to make another materially different product”.
The requirement is still deemed proper and is therefore made FINAL.
Claim 6 is cancelled.
Claims 1-5, 7-14 and 18-20 are 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 requirement in the reply filed on 09/21/2026.
Claims 15-17 are under current examination.
Priority
This application is a CON of Application 17/298,528, filed 05/28/2021, now abandoned. Application 17/298,528 is a national stage entry of PCT/US2019/062704, filed 11/21/2019, which claims priority to US PRO 62/776,965, filed 12/07/2018.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/21/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 112(a)-Scope of 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.
Claims 15-17 are rejected under 35 U.S.C. 112(a), because the specification, while being enabling for preparing a solid form or solid crystal form of N-methylisoindigo having and X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 7.71°, by precipitating a crystalline form from a solution comprising glacial acetic acid, N-methylisatin, oxindole, and HCl, and recrystallizing from glacial acetic acid does not reasonably provide enablement for preparing the solid form or solid crystal form from any solution under any reaction or recrystallization conditions. 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 without undue experimentation. MPEP 2164.01(a), citing In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), sets out the factors to consider whether experimentation is undue, which include:
(A) The breadth of the claims. Claim 15 recites a process for preparing a solid form or solid crystal form of N-methylisoindigo (Crystal Form I) having an X-ray powder diffraction pattern comprising a peak in terms of 2-theta at about 7.71°, the process comprising precipitating a crystalline form from a solution comprising an organic solvent. The claim does not require any reactants or components in the solution other than an organic solvent, does not recite any specific reaction or precipitation conditions, and does not limit the identity of the organic solvent. Claim 16 requires the presence of glacial acetic acid, and claim 17 requires the presence of N-methylisatin, oxindole, and/or HCl.
The only required active step in the method is precipitating a crystalline form from a solution comprising an organic solvent (claim 15), glacial acetic acid (claim 16), and one of N-methylisatin, oxindole, or HCl (claim 17). Thus, the scope of the claims is extremely broad.
(B) The nature of the invention. The claims are drawn to a process of preparing a solid or solid crystal form of N-methylisoindigo having a particular peak in the X-ray powder diffraction pattern. The instant specification discusses that N-methylisoindigo (or meisoindigo) has therapeutic efficacy against various autoimmune/inflammatory diseases and cancers (see paragraphs [006] and [008]).
(C) The state of the prior art. The prior art of Seo et al. (“Facile Synthesis of Isoindigo Derivatives from 3-Indolyl-2-Oxindoles with DDQ”; included on IDS submitted 11/21/2024) teaches that, in general, isoindigo derivatives have been synthesized by an acid-catalyzed condensation reaction of isatin with oxindole, tris(diethylamino)phosphine-mediated carbene dimerization of isatin, and palladium-catalyzed cascade dual annulations of diarybut-2-ynediamides (pg. 1519, column 1, paragraph 2), and further demonstrates the formation of meisoindigo via reactions of 3-indolyl-2-oxindoles with DDQ in the presence of TFA (see particularly Scheme 1 at pg. 1520). Each of these methods require specific reactants and reaction conditions.
The prior art of Brown (WO 2013/142817 A2; included on IDS submitted 11/21/2024) demonstrates that varying process parameters in the synthesis of meisoindigo, such as replacing HCl with a catalytic amount of sulfuric acid or trifluoroacetic acid, can affect the drug content and purity of the resulting product (see paragraphs [0362]-[0383], particularly paragraphs [0373]-[0374] and Table 4).
The prior art of Khoshkhoo et al. (“Crystallization of polymorphs: the effect of solvent” J. Phys. D: Appl. Phys. 1993, 26, B90-B93) teaches that in studying the crystallization of polymorphs in a model drug compound, it was discovered that not all of the known polymorphic forms can be crystallized from any given solvent by varying the supersaturation; some solvents selectively favor the crystallization of a particular form or forms, and 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 (see particularly Abstract and pg. B93, column 1, paragraphs 2-3). Thus, the prior art suggests that solvent choice can affect which polymorph of a drug will crystallize.
(D) The level of one of ordinary skill. The level of ordinary skill in the art is assumed to be that of one having knowledge and/or experience in the preparation of crystalline forms of pharmaceutical ingredients, particularly those that treat conditions such as cancer and autoimmune disease. While the relative skill of those in the art is high, likely that of a Ph.D. or other advanced degree, that factor is outweighed by the unpredictable nature of the art.
(E) The level of predictability in the art. There is well-known unpredictability of chemical reactions in the field of chemistry generally (see MPEP 2164.03). Further, as noted above, the prior art of Brown demonstrates that changing process parameters in the synthesis of meisoindigo, such as replacing HCl with a catalytic amount of sulfuric acid or trifluoroacetic acid, can affect the drug content and purity of the resulting product. As further noted above, the prior art of Khoshkhoo et al. suggests that not all polymorphic forms of a compound can be crystallized from any given solvent, and some solvents selectively favor the crystallization of a particular form or forms.
Thus, in the context of preparing a solid form of N-methylisoindigo having a particular X-ray diffraction pattern from any solution comprising any organic solvent via any crystallization conditions, the level of unpredictability is extremely high.
(F) The amount of direction provided by the inventor and (G) The existence of working examples. Applicant has provided one example of the preparation of Crystal Form I from starting materials N-methylisatin and oxindole stirred and heated in the presence of glacial acetic acid and concentrated HCl and recrystallized from glacial acetic acid (see paragraphs [0088]-[00100]). Applicant does not provide examples or guidance to prepare Crystal Form I from any other materials or via any other reaction or recrystallization conditions. On the contrary, Applicant demonstrates that six samples prepared with indole as a starting material and recrystallized under various conditions (methanol/water, methanol, ethyl acetate and ligroin, ethyl acetate, ethyl alcohol and water, and ethyl alcohol) were structurally different than Crystal From I (see paragraphs [00132]-[00146]). Thus, the specification fails to provide sufficient direction to practice the invention in its “full scope”.
(H) The quantity of experimentation needed to make or use the invention. As set forth above, the scope of the claims is extremely broad, there is known unpredictability in the chemical arts and particularly in achieving a particular polymorph of a given compound, and the specification lacks guidance on preparing the Crystal Form I of N-methylisoindigo outside of the specific conditions exemplified. In order to practice the full scope of Applicant’s invention, it would be necessary for one of ordinary skill in the art to design and conduct an exhaustive amount of reactions and recrystallization experiments to achieve a Crystal Form I of N-methylisoindigo. Therefore, in order to practice the full scope of the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In view of the consideration of all of the above Wands factors, the specification does not reasonably enable a person of ordinary skill in the art to practice the invention commensurate in full scope with the instant claims without undue experimentation.
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.
Claims 15-17 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 15 recites “a solid form or solid crystal form of N-methylisoindigo (Crystal Form I)”; it is unclear if “Crystal Form I” in parentheses is intended to be a further limitation of the solid crystal form or not, and if so, it is unclear what requirements a crystal must meet in order to satisfy being of “Crystal Form I”. Does a crystal of N-methylisoindigo having an X-ray diffraction pattern comprising a peak, in terms of 2-theta, at about 7.71° satisfy being of Crystal Form I or is there some other requirement?
Claims 16-17 are rejected under 35 U.S.C. 112(b) by virtue of their dependency on indefinite claim 15, and failure to cure the deficiency noted above.
Claim Rejections - 35 USC § 102/103
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.
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.
Claims 15-17 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Wang et al. (US 6,933,315 B2, patented August 23, 2005, included on IDS submitted 11/21/2024), hereafter “Wang”, as evidenced by Zhou et al. (“The Effects of Polymorphism on Physiochemical Properties and Pharmacodynamics of Solid Drugs” Current Pharmaceutical Design, 2018, 24, 2375-2382), hereafter “Zhou”.
Wang discloses the synthesis of meisoindigo (N-methylisoindigo, see Fig. 1) which results in brick-like red crystal precipitates (column 18, Example 3). The crystals are synthesized by reacting equimolar amounts of 2-hydroxindole and N-methyl-indolinyl-diketone in glacial acetic acid and hydrochloric acid with heating and stirring, and bulk crystal precipitates are formed (consistent with the active method steps of the instant claims). The resulting bulk crystal precipitates are filtered, washed, and recrystallized from glacial acetic acid.
Wang does not explicitly disclose that the meisoindigo prepared by the process has an X-ray diffraction pattern comprising a peak, in terms of 2-theta, at about 7.71°. However, the process of Wang anticipates the active method steps recited, and the process is substantially identical to that disclosed in the specification of the instant invention which results in a form of N-methylisoindigo having the claimed X-ray diffraction pattern (paragraphs [0095]-[0099]). The instant specification notes that all samples from the same manufacturing procedures include the same crystal form of the compound with the one peak at 2θ=7.71° dominating (paragraph [00121]). Further, the reported melting points of the resulting crystals are the same in both cases; the melting point of the recrystallized product of Wang is reported to be 236-237 °C (column 18, Example 3), while that of the instant invention is 235-237 °C (paragraphs [00102] and [00115] and Table 1). As evidenced by Zhou, polymorphs of the same solid drugs generally exhibit different melting points (pg. 2378, section 3.2).
Absent evidence to the contrary, the solid form of N-methylisoindigo prepared by the method of Wang is the same as that of the instant invention, as it is synthesized by a substantially identical process; therefore, it will have the same physical properties including X-ray powder diffraction pattern. From MPEP 2112.01 I. “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)”.
Further, per MPEP 2112 III., “Where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103. "There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C. 103 and for anticipation under 35 U.S.C. 102." In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102 and 103 rejection is appropriate for these types of claims as well as for composition claims”, and per MPEP 2112 V, “"[T]he PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. 102, on ‘prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same." In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977) (footnote and citation omitted)”.
Thus, the claims are anticipated by or, in the alternative, obvious over Wang.
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 15-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-9 of U.S. Patent No. 6,933,315 B2 (included on IDS submitted 11/21/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
Both the instant claims and those of U.S. Patent No. 6,933,315 B2 recite a method of preparing meisoindigo comprising forming a precipitate from a solution comprising glacial acetic acid, oxindole, and N-methylisatin.
The claims of U.S. Patent No. 6,933,315 B2 do not recite that the meisoindigo prepared by the process has an X-ray diffraction pattern comprising a peak, in terms of 2-theta, at about 7.71°. However, the claims of U.S. Patent No. 6,933,315 B2 recite active method steps consistent with those instantly claimed, and the process is substantially identical to that disclosed in the specification of the instant invention which results in a form of N-methylisoindigo having the claimed X-ray diffraction pattern (paragraphs [0095]-[0099]).
Absent evidence to the contrary, the solid form of N-methylisoindigo prepared by the method recited by U.S. Patent No. 6,933,315 B2 is the same as that of the instant invention, as it is synthesized by a substantially identical process; therefore, it will have the same physical properties including X-ray powder diffraction pattern. From MPEP 2112.01 “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)”.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUDITH M KAMM whose telephone number is (703)756-4575. The examiner can normally be reached M-F 8:00 am-4:30 pm EST.
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, Bethany Barham can be reached at (571)272-6175. 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.
/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611
