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 .
Priority
The instant application is a 35 USC 371 National Stage filing of international application PCT/US2021/057710, filed November 2, 2021, which claims the benefit of an effective US filing date under 35 USC 119(e) from provisional applications 63/109,940, filed November 5, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) dated November 13, 2023 and October 22, 2024 were in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the IDS documents were considered and signed copies of the 1449 forms are attached.
Election/Restrictions
Applicant’s election without traverse of the invention of Group I, claims 1-16, drawn to a method of treating a BTK mediated disorder, in the reply filed on October 21, 2025 is acknowledged. Further, Applicant’s election without traverse of lymphocytic lymphoma in the same reply is also acknowledged. The elected species reads on each of claims 1-16 within the elected group. The restriction requirement is still deemed proper and is therefore made FINAL.
In accordance with the MPEP, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended (see MPEP 803.02). If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. Id. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. Id. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final. Id.
As indicated above, the examiner searched the compound based on the elected species above, wherein: the elected species was found to be rendered obvious by the prior art. Therefore, the scope of the search and consideration was expanded in accordance with MPEP 803.02 to also include the compounds described in the rejections herein. Since this scope was not found to be allowable, the scope of the search and examination was not extended further, although any additional anticipatory compounds in the same prior art, discovered incidental to the examination of the elected species, are also included in the rejections herein.
Status of Claims
Currently, claims 1-23 are pending in the instant application and under consideration herein. Claims 17-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention and/or species.
Claims 1-16 read on an elected invention and species and are therefore under consideration in the instant application to the extent that they read on the elected embodiment.
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 15-16 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.
Claims 15-16 recite the limitation "or hematological malignancy" in the second line of each claim. There is insufficient antecedent basis for this limitation in the claim since claim 12 does not contain any recitation of a “hematological malignancy.”
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 1-12 and 15-16 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 of chronic lymphocytic leukemia (CLL), Richter's Transformation (RT), small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), primary central nervous system (CNS) lymphoma, secondary central nervous system (CNS) lymphoma, marginal zone lymphoma (MZL), and Waldenstrӧm's macroglobulinemia (WM), does not reasonably provide enablement for a method of treating all of the diseases encompassed by the claim to treating any and all “BTK mediated disorders” (claim 1), including cancer generally. 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 or us the invention commensurate in scope with these claims.
As stated in the MPEP 2164.01 (a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
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
The nature of the invention is a method of treating any and all conditions mediated by BTK comprising administering a compound of Formula (I). Support for the intended use is in the disclosure that the claimed compound is capable of inhibiting BTK. No data, in vitro or otherwise, is provided, although the disclosure sets forth planned dose escalation studies.
The state of the prior art and the predictability or lack there of in the art
The state of the prior art is that the pharmacological art involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific disease by what mechanism). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The instant claimed invention is highly unpredictable as discussed below:
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to therapeutic effects of any condition mediated by MCL-1 inhibition, whether or not the condition is affected by the instant compounds’ activity would make a difference.
For example, Applicants’ claim is drawn to a method of treating cancer. The state of the prior art is that cancer therapy remains highly unpredictable. The various types of cancers have different causative agents, involve different cellular mechanisms, and consequently, differ in treatment protocol. Cancer is a disease characterized by a population of cells that grow and divide without respect to normal limits, invade and destroy adjacent tissues, and may spread to distant anatomic sites through a process called metastasis (URL:http://en.wikipedia.orq/wiki/ Cancer>). Most cancers are named for where they start. For example, lung cancer starts in the lung, and breast cancer starts in the breast. Symptoms and treatment depend on the cancer type and how advanced it is (URL: <http://www.nlm.nih.gov/medlineplus/cancer. html>>).
It is known that the challenge of cancer treatment has been to target specific therapies to pathogenetically distinct tumor types, that cancer classification has been based primarily on morphological appearance of the tumor and that tumors with similar histopathological appearance can follow significantly different clinical courses and show different responses to therapy (Golub et al. page 531). Treatment may include surgery, radiation, chemotherapy, immunotherapy, monoclonal antibody therapy, etc. Furthermore, it is known that chemotherapy is most effective against tumors with rapidly dividing cells and that cells of solid tumors divide relatively slowly and chemotherapy is often less effective against them. It is also known in the prior art (Lala et al. page 91) that the role of NO in tumor biology remains incompletely understood with both the promotion and inhibition of NO mentioned for the treatment of tumor progression and only certain human cancers may be treated by selected NO-blocking drugs. These example shows that there are different cellular mechanisms, the unpredictability in the art and the different treatment protocols. Because "cancer" refers to a class of diseases, it is unlikely that there will ever be a single "treatment for cancer".
There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The amount of direction or guidance present and the presence or absence of working examples
The only direction or guidance present in the instant specification is minimal. There are no working examples present for treating any and all disease mediated by BTK.
Test assays and procedure are provided in the specification which describe a plan for dosage escalation studies.
Receptor activity is generally unpredictable and the data provided is insufficient for one of ordinary skill in the art in order to extrapolate to the other compounds of the claims. It is inconceivable as to how the claimed compounds can treat the extremely difficult diseases embraced by the instant claims.
Applicants have not provided any competent evidence or disclosed tests that are highly predictive for the pharmaceutical use of the instant compounds. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The breadth of the claims
The breadth of the claims is a method of treating all of the diseases listed in the instant claims that are mediated by BTK (Bruton’s tyrosine kinase). Notably, this includes any condition associated with either the under-expression or over-expression of BTK, although the claimed compound is only known to have the ability to inhibit BTK.
The quantity of experimentation needed and the level of the skill in the art
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine what diseases would be benefited by the effects of inhibiting BTK and would furthermore then have to determine whether the claimed compound in the instant invention would provide effective treatment of each of the diseases.
The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated by the compound encompassed in the instant claims, with no assurance of success.
This rejection can be overcome, for example, by amending the claim to read on the subject matter that Applicants' specification are enabled for as indicated above.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-3 and 5-16 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Woyach et al. (citation 3 on 10/22/24 IDS).
Woyach et al. discloses a dose escalation study for ARQ531 (identical to the compound of instant Formula (I)) in the treatment of BTK mediated disorders to determine dosage and treatment schedule. Patients treated in the reference had relapsed/refractory CLL/SLL, B-cell NHL or Waldenstrom’s macroglobulinemia, as required by instant claims 12-15. The reference further teaches the use of ARQ 531 as an inhibitor of ibrutinib-resistant C481S-mutant BTK, as required by instant claim 16 (see Introduction). Patients in the Woyach study received ARQ 531 orally once daily (which reads on claims 5-6 and 9), continuously in 28 day cycles (which reads on instant claims 7-8 and 10-11) of 5, 10, 20, 30, 45, 65 and 75 mg QD (once a day). Notably, there is no range defined for the instantly claimed “about 80 mg” such that the dosages on the upper end of the treatment groups taught by Woyach anticipate the instantly claimed dosage amount. Since the prior art teaches all required features of the instant claims, the claims are anticipated.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/358233 (“the ‘233 publication”) in view of Woyach et al. (citation 3 on 10/22/24 IDS).
Determining the scope and contents of the prior art
The ‘233 publication teaches a method of treating a BTK mediated disorder, comprising administering to a subject in need thereof (paragraph [0009]) a compound of instant formula (I) (paragraph [0221]). The reference discloses that BTK mediated disorders include cancers, B-cell lymphoma, leukemia, and other hematological malignancies. Additionally, the ’233 publication teaches that the compound inhibits kinase activity of a mutant BTK, such as drug-resistantmutant BTK harboring a drug-resistance mutation, for example C481S mutation. The prior art further directs towards the treatment of patients not responding to a BTK inhibitor or relapsing after initial treatment with a BTK inhibitor. The instantly claimed compound is more potent than several other BTK inhibitors, including ibrutinib. Regarding the claimed dosage, the prior art teaches that dosages range from about 0.01mg/kg per day to about 5000 mg/kg per day, thereby completely encompassing the dosage range recited in the instant claims.
Ascertaining the differences between the prior art and the claims at issue
The difference between the instant invention and the prior art is that the prior art does not teach a specific example where the dosage range or length of treatment is disclosed.
Resolving the level of ordinary skill in the pertinent art
To this end, it is noted that MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.’" KSR, 550 U.S. at ___, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
Woyach et al. discloses a dose escalation study for ARQ531 (identical to the compound of instant Formula (I)) in the treatment of BTK mediated disorders to determine dosage and treatment schedule. Patients treated in the reference had relapsed/refractory CLL/SLL, B-cell NHL or Waldenstrom’s macroglobulinemia. Patients received ARQ 531 orally once daily, continuously in 28 day cycles of 5, 10, 20, 30, 45, 65 and 75 mg QD (once a day). Woyach et al. provides, at the very least, a teaching of treatment length and suggestion for the relative area within the broad dosage range for a person of ordinary skill to optimize dosage.
MPEP 2144.05(I) provides that "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). See also In re Harris, 409 F.3d 1339, 74 USPQ2d 1951 (Fed. Cir. 2005) (claimed alloy held obvious over prior art alloy that taught ranges of weight percentages overlapping, and in most instances completely encompassing, claimed ranges; furthermore, narrower ranges taught by reference overlapped all but one range in claimed invention). Thus, the prior art ranges render the dosages of the instant claims obvious.
Accordingly, based on the teachings of the MPEP and KSR above, by employing the rationale in (B), (D), (E) or (G) above, it would have been obvious for one of ordinary skill in the art to treat BTK disorders, including the particular cancers recited in claims 13-14 and taught by the ‘233 publication, utilizing a compound of Formula (I) at a dosage of about 80 to about 160 mg/day, including the “about 100 mg per day” required by instant claim 4. The ’233 publication discloses that dosage can range from about 0.01mg/kg per day to about 5000 mg/kg per day, with Woytach et al. narrowing down the range for experimentation, such that it would have been considered routine optimization to arrive at the dosages and schedule recited in the instant claims. There would have been a reasonable expectation of success in treating these diseases since the same Compound was already known in the art for the treatment of diseases associated with BTK. The instantly claimed invention would have therefore been obvious to a person of ordinary skill before the filing of the instantly claimed invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alicia L. Otton whose telephone number is (571)270-7683. The examiner can normally be reached on Monday - Thursday, 8:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Fereydoun Sajjadi can be reached on 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699