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 (I) in the reply filed on 07/23/2025 is acknowledged. A search directed to elected subject matter, i.e., crystal form I of compound A, identified CN110407856B (herein the CN’ document”) as the closest prior art. The CN’ document teaches compound R29
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. (See Example 3.) However, the CN’ document does not teach or suggest the claimed X-ray powder diffraction pattern of crystal Form I. Accordingly, the previously issued restriction requirement dated 05/28/2025 is withdrawn.
Priority
The present application is a National Stage filing under 35 U.S.C. 371 of International PCT Application No. PCT/CN2021/094362, filed on May 18, 2021, which claims the priority of the Chinese Patent Application No. 202010421308.9, filed on May 18, 2020.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on January 27, 2026.
Claims 1-12, 106-108, 110, 117-118, 120, 125, and new claims 127-134 are pending and under examination. Claims 13-105, 109, 111-116, 119, 121-124, and 126 are canceled.
Response to Arguments
Applicant’s arguments filed 01/27/2026 have been fully considered. Rejections and objections not reiterated form previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Claim Objections
Claim 3 is objected to because of the following informalities: the trailing period after “54.1.” inside the table. The trailing period appears to be extraneous and render the presentation of the numerical value unclear or inconsistent. Appropriate correction is required.
Claims 3-5 are objected as being depending from 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. It is noted that claim 3 is additionally subject to a separate objection as set forth above, and this dependency objection will apply to claim 3 upon correction of that issue.
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 117, 118, 125 and 133-134 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 117 recites a pharmaceutical composition comprising microcrystalline cellulose and mannitol in an amount of 65-95% by weight, followed by the parenthetical expression “(2:1, by weight).” It is unclear whether the recited ratio of 2:1 is a required limitation of the claim or merely an exemplary or explanatory of the preceding limitation. Therefore, the metes and bounds of the claim are not reasonably certain.
Claim 118 depends from claim 117 and recites amounts (about 45 mg of microcrystalline cellulose and about 25 mg of mannitol) corresponding to a ratio of approximately 1.8:1. Due to the ambiguity in claim 117 as to whether the 2:1 ratio is required; it is further unclear whether the subject matter of claim 118 falls within the scope of claim 117.
Claim 125 recites “a disease mediated by ALK and ROS1 kinases and mutants thereof.” It is not clear what is encompassed by “mutants thereof,” as the specification does not define or otherwise delimit the scope of mutations included. For example, it is unclear whether the term encompasses all possible mutations of ALK and ROS1, including point mutation, insertions, deletions, fusions, or other variants, or whether any functional limitations apply. Additionally, it is unclear the claim requires a disease mediated by both ALK and ROS1, or whether mediation by either ALK or ROS1 (or their respective mutants) is sufficient. Accordingly, the metes and bounds of the claims subject matter are not reasonably certain.
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.
Claim 133 is 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 133 depends from claim 117, which requires a pharmaceutical composition comprising microcrystalline cellulose and mannitol. However, claim 133 recites a composition comprising microcrystalline cellulose and lactose monohydrate and does not include mannitol. 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.
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 1-2, 6-12, 106-108, 110, 117-118, 120, 125, and 127-134 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.
The specification must reasonably convey to one of ordinary skill in the art that the inventor had possession of the claimed subject matter as of the filing date. See MPDP 2163.
The instant claims define the crystal Form I by reciting only a limited subset of X-ray powder diffraction (XPRD) peaks (e.g., selected 2θ values). However, the specification describes the crystal form using a complete XRPD pattern, as shown in figure 1 and Table 3.1, which included numerous additional peaks and corresponding relative intensities.
The specification therefore demonstrates possession of a specific crystal Form characterized by a full diffraction fingerprint, but does not reasonably convey possession of all crystalline forms that merely exhibit the limited subset of peaks recited in the claims.
Because multiple distinct crystalline forms may share a subset of XPRD peaks while differing in other peaks and/or intensities, the claims encompass crystalline forms that are not demonstrated to be in the possession of the inventors. (See Tables below.)
Crystal Form I Crystal Form V
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474
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434
590
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Wang et al. cited below supports that assertion that if polymorphs differ significantly, then defining a crystal using only a few peaks is overbroad. Accordingly, the written description requirement is not satisfied.
Claims 1, 125, and 134 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 treating NSCLC and lymphoma, does not reasonably provide enablement for treating the full scope of the disease recited in the claim. 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.
Claim 125 recites a method of treating diseases mediated by ALK and ROS1 kinases mutants thereof in a subject, encompassing a broad range of diseases including, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer, large intestine cancer, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, and cystic fibrosis.
Application of Wands’ Factors
1) Scope/Breadth of the claims
The claims encompass multiple mechanistically distinct pathways, both cancer and non-cancer conditions, and disease not established to be mediated by ALKJ/ROS1 pathway.
2) State of the art
Wang et al. (US10,543,199 B2) teaches that ALK and ROS1 inhibitors (e.g., crizotinib) are primarily used in oncology, particularly non-small cell lung cancer (NSCLC). Want et al. also teaches therapeutic outcomes are unpredictable, even with oncology due to acquired resistance, off-target effects, and safety and tolerability limitations. (See lines 24-58 of column 1.) Thus, the art demonstrates narrow applicability, cancer-focused, and unpredictability even within that limited scope.
3) Nature of the invention
Pharmaceutical method of treatment involving kinase inhibition in complex biological systems.
4) Level of skill in the art
High, but insufficient to bridge the gaps across unrelated disease mechanisms.
5) Predictability of the art
Low-kinases signaling pathways are complex and disease-specific.
6) Amount of guidance in the specification
Minimal or none-no teaching for non-oncology indications and oncology indication outside of NSCLC and lymphoma.
7) Presence of absence of working examples
Limited or absent of working examples for any treatment with the crystal form I claimed.
8) Quantity of experimentation required.
Extensive experimentations would be required to test the crystal form I in each disease state and would be required independent investigation for each.
The specification at most based-on Wang et al. enables for treatment of ALK/ROS1-driven NSCLC and lymphoma, but does not enable for the full scope of the disease recited. Accordingly, undue experimentation would be required to practice the claimed invention across the full scope, and the claims are not enabled.
Claims 106-132 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 composition recited in claims 133, does not reasonably provide enablement for the full scope of the composition recited in claim 106-132. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
The claims are directed to pharmaceutical compositions comprising a crystal Form I in combination with broadly defined classes and wide concentration ranges of excipients.
The specification provides only two tablet formulations (5 mg and 25 ng) as depicted below:
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No guidance regarding variation across ranges, excipient substitution, and polymorph stability in different formulations.
Application of Wands’ Factors
1) Breadth and scope of the claims
The claims encompass broad API concentration ranges, multiple excipients classes and alternatives with broad concentration ranges, and numerous potential formulations.
2) State of the Art
The art (Clavier, Current Opinion: 2024 Vol:16, Issue 6) demonstrates that polymorphs significantly affect solubility, dissolution rate, stability, and bioavailability. Different polymorphs of the same compound can exhibit different pharmaceutical behavior, despite identical chemical composition. Polymorphs forms are sensitive to formulation conditions, including excipients selection, processing conditions, and storage. Polymorphs may undergo phase transition, recrystallization, and conversion to less stable forms. (See whole document.) Additionally, Wang et al (cited above) shows that variability and unpredictability in therapeutic outcome even within known applications of the compound. (See lines 24-58 of column 1.)
3) Nature of the invention
Pharmaceutical compositions involving a specific crystal polymorph, which is highly sensitive to formulation variables.
4) Level of skill in the art
High, but insufficient to predict polymorph behavior across all claimed compositions.
5) Predictability of the art
Low-polymorphs behaviors is known to be formulation-dependent and unpredictable.
6) Amount of guidance in the specification
Minimal-limited to two specific examples.
7) Presence or absence of working examples
Only two examples, not presentative of the full scope.
8) Quantity of experimentation required
Substantial-would require extensive formulation screening to determine stable and effective compositions.
Given the sensitivity of polymorphic forms to formulation conditions and the lack of guidance in the specification, a person of ordinary skill in the art would be required to engage in undue experimentation to practice the full scope of the claimed compositions.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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