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 .
Detailed Action
Claims 1-10 are currently pending.
Claim interpretation
Claims 7-9 are interpreted to include only carriers, glidants, diluents, excipients, or stabilizers which are solid or otherwise do not destroy the polymorphic structure of Form A of Compound A which is required to be present in the claimed composition.
Claim Objections
Claim 7 is objected to because of the following informalities:
“as active ingredient” should read “as an active ingredient”
The comma after “Compound A” should be deleted
“carrier, glidant, diluent, excipient or stabilizer” should be pluralized following the phrase “one or more”.
Appropriate correction is required.
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.
Claims 8-9 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
the treatment—not including prophylactic treatment—of MCL-1-associated cancer, autoimmune diseases, and diseases of the immune system,
does not reasonably provide enablement for
the prophylactic treatment of cancer, auto-immune diseases and diseases of the immune system or
treatment—any form of treatment—of non-MCL-1-associated cancer, autoimmune diseases, and diseases of the immune system.
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.
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
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,
7. the quantity of experimentation needed, and
8. the level of the skill in the art.
The nature of the invention (1) and breadth of the claims (6)
The nature of the invention and breadth of Claims 8-9 is the treatment, including the prevention of cancer, auto-immune diseases, and diseases of the immune system.
The last paragraph of Page 16 of the specification provides that the term “treatment” includes “prophylactic treatment” or prevention.
The state of the prior art (2) and the predictability or lack thereof in the art (3)
Xiang (OncoTargets and Therapy 2018:11 7301–7314) teaches only “36% of breast cancer and 54% of lung cancer specimens exhibit elevated levels of MCL-1 expression” (Page 7301, Para 3). It is unclear then how an MCL-1 inhibitor would reduce/ameliorate the symptoms of the cancers not associated with MCL-1 overexpression, let alone prevent them.
Regarding autoimmune diseases, Pierson (Nat Immunol 14, 959–965 (2013).) concludes “Mcl-1 was essential for Treg cell survival. Furthermore, Mcl-1 appears to represent a rheostat for controlling the Treg cell homeostatic niche…This role of the Mcl-1 and Bim axis in driving the return of Treg cells to homeostatic levels is a potential intervention point for therapeutic manipulation” (Page 964, Last Para). The conclusion is based on the following finding; “Mcl-1 was critical for survival of Treg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity” (Abstract). Thus, Pierson demonstrates autoimmunity can result from conditions not mediated by MCL-1 or the overexpression thereof, but rather a lacking altogether. It is unclear how then an inhibitor of the claimed invention might serve to prevent or therapeutically treat conditions not associated with MCL-1 but instead its underexpression.
Several difficult diseases are taught to be difficult to prevent generally, let alone through Mcl-1 inhibition specifically. For example, rheumatoid arthritis (RA) is a complex disease without a well-established etiology. Wang (Scandinavian Journal of Immunology. Volume 75, Issue 2 pp. 203-209 (2011)) clearly teaches “the pathogenesis of RA is still unclear” (Page 203, Introduction). Wang further teaches “Gaq controlled the apoptosis of RA PBLs through regulating the activity of Mcl-1 and caspase-3” (Abstract). See Figure 3 on Page 207. Therefore, Wang does imply treatment with Mcl-1 inhibition is a possible therapeutic route but establishes that Mcl-1 elevation is likely a consequence of upstream effects rather than some causal factor. Treating such downstream effects therapeutically is not a route for preventing the disease.
The amount of direction or guidance present (4) and the presence or absence of working examples (5)
Compound A is described as an MCL-1 inhibitor previously in “WO 2015/097123” (Specification: Page 2). However, applicant does not disclose how an MCL-1 inhibitor might ameliorate the symptoms of cancers or immune diseases not associated with MCL-1—let alone how such diseases might be prevented through the methods of Claims 8-9.
Examples 1-20 of the specification are largely related to preparation and characterization of crystal forms rather than biological properties.
The quantity of experimentation needed (7)
The quantity of experimentation needed is extremely difficult, novel, and undue; the ability of the examined method to reduce/ameliorate the symptoms of non-MCL-1 associated diseases or prevent any of the claimed diseases is known to be unworkable in view of the above the art, or likely to fail as a therapeutic treatment in the diseases like breast cancer wherein elevated MCL-1 is not characteristic of 64% of variants. These experiments also would not resolve the ability of the claimed polymorph to treat diseases which are not known to be preventable or whose pathogenesis is not known to be associated with Mcl-1. The diffraction experiments disclosed in the specification of the application do not enable the broad scope of treatment which includes prevention.
The level of skill in the art (8)
The level of skill in the pharmaceutical art is high. However, even one of the highest skill in the art would find it unduly burdensome to determine which diseases of the broad scope claimed might be treated with even the one polymorph claimed. Said artisan would need to determine which diseases are mediated by MCL-1 and which diseases are treated either prophylactically or therapeutically with the claimed compound. Several specific embodiments like breast cancer are taught in Xiang to express variable MCL-1 levels which further complicates the question of determining therapeutic treatment and prevention. Wang suggests that autoimmune diseases are not preventable through mediation of downstream actors like Mcl-1 as well.
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.
Claim 6 contains the trademark/trade names “PANalytic” (Serial Number 76391600), “Empyrean” (77934511), and “PIXcel 1D” (86776121). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe diffractometers used in the characterization of the examined polymorphs and, accordingly, the identification/description is indefinite. It is further unclear what “the spinner transition mode” is with respect to such indefinite trademarked terms. (See corresponding Justia Trademark NPL attachments for further trademark information.)
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-6 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites “crystalline Form A of…Compound A”. Claims 2-6, depending on Claim 1, describe the same crystalline Form A and recite additional explicit data which are inherent properties of Form A of Compound A. The recited data and features are not further limiting. Form A, as recited in Claim 1, necessarily possesses all of the properties described in the dependent claims whether such properties are explicitly recited or implicitly included in Claim 1. Therefore, the characteristic features of Form A are included in Claim 1 by virtue of reciting “crystalline Form A”, and Claims 2-6 only explicitly characterize those features which again are necessarily inherent to Form A in Claim 1. As such, the scope of Claim 1 is not further limited by Claims 2-6. Additionally, Example 15 on Page 29 characterizes the synthesis and XRPD properties of the single polymorph described as Form A of Compound A.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Allowable Subject Matter
The closest prior art is disclosed in Szlavik (WO2016207225, 9/24/2024 IDS). Szlavik teaches the preparation of claimed Compound A, washed with HCl and extracted with DCM (Page 35, Preparation 12). Szlavik does not teach recrystallization with the solvents described in applicant’s specification Example 15 which include DME and 2-methltetrahydrofuran. Szlavik does not characterize any crystal polymorphs. Applicant describes multiple forms of Compound A (Specification: Figures 1-13). Therefore, one of skill in the art could not reasonably expect or predict that Form A would result from the preparation of Szlavik, absent the necessary solvents for crystallization taught by applicant. The crystal form and methods and compositions thereof are free of the prior art.
Conclusion
Claims 1 and 10 are allowable. Claim 7 is objected to. Claims 2-6 and 8-9 are rejected.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Richard G. Peckham whose telephone number is (703)756-4621. The examiner can normally be reached 8:30am - 4:30pm EST.
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/RICHARD GRANT PECKHAM/Examiner, Art Unit 1627
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