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
This application is a 371 of PCT/CA2023/050281 03/03/2023, which claims priority to US Provisional Application No. 63/316,153 03/03/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/17/2025 and 06/24/2026 has been considered by the examiner.
Status of Claims
Claims 1-19 and 22 are pending and under examination. Claims 20-21 and 23-50 are canceled.
Claim Rejections - 35 USC § 112
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 1-19 and 22 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 certain hematologic malignancies, particularly B-cell lymphoma, DLBCL (e.g., Diffuse large B cell lymphoma (DLBCL), leukemia (e.g. acute myeloid leukemia) via the oral administration of PCLX-001 20-210 mg per day, does not reasonably provide enablement for the full scope of cancer claimed in claim 1 and 19 and the full scope of oral dosage form claimed. 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.
The claims are directed to methods of treating cancer by orally administering OCLX-001 at daily dosages ranging from 20 mg/day through 420 mg/day. Independent claim 1 encompasses treatment of cancer generally, while claim 19 further encompasses an extensive list of biologically distinct malignancies, including diffuse Large B Cell Lymphoma (DLBCL), refractory DLBC, lymphoma, leukemia, myeloma, breast cancer, small cell lung cancer, non-small cell lung cancer cells; melanoma, adenocarcinoma, pancreas cancer, bladder cancer, ovarian cancer, brain cancer, colon cancer, neuroblastoma, carcinoma, endometrial cancer, sarcoma, thyroid cancer, fibrosarcoma, oral cancer, tongue cancer, nasopharynx cancer, larynx cancer, esophageal cancer, germ cell cancer, stomach cancer, hepatocellular cancer, biliary tract cancer, small intestinal cancer, testis cancer, epidermoid cancer, cervical cancer, kidney cancer, prostate cancer, or pharynx cancer, and others. Accordingly, the claims are broad both with respect to the therapeutic scope (the cancers treated) and the dosage scope (20 mg/day through 420 mg/day). The present specification does not reasonably enable either aspect of the claimed breadth without undue experimentation.
I. Breadth of the claimed Therapeutic Scope
The breadth of the therapeutic claims weighs heavily against enablement. Claim 1 broadly recites treating “cancer” without limitation as to cancer type. Claim 19 further illustrates the breadth intended ay Applicant by expressly reciting numerous unrelated homologic and solid malignancies.
These diseases are medically and biologically distinct and involve different oncogenic drivers, signaling pathways, tumor microenvironment, mechanism of progression, and mechanism of therapeutic resistance. Consequently, demonstrating therapeutic efficacy for one cancer does not reasonably establish therapeutic efficacy across all of the claimed cancers.
II. Limited Therapeutic Guidance Provided by the Specification
The specification provides only limited therapeutic guidance. Although, the specification contains pharmacokinetic analyses and preclinical studies, the clinical disclosure consists primarily of observation involving only three patients:
tow patients having relapsed/refractory diffuse B-cell lymphoma; and
one patient having metastatic leiomyosarcoma.
Therapeutic outcomes among these patients were inconsistent. One patient
experienced disease progression. One patent demonstrated regression of a hepatic metabolic lesion. One patient experienced progressive disease. Thus, the only clinical efficacy evidence consists of one patient demonstrating partial radiologic improvement, while the remaining two patients experienced disease progression. Accordingly, the specification does not demonstrate therapeutic efficacy across the extensive number of cancers encompassed by the claims. Instead, much of the disclosure emphasizes pharmacokinetic measurement, including Tmax, Cmax, AUC, half-life, dose proportionality, and though concentrations, together with in vitro inhibition of cultured cancer cells. However, favorable pharmacokinetics properties and in vitro inhibition of cultured cancer cells do not reasonably establish therapeutic efficacy throughout the entire claimed therapeutic scope.
III. Breadth of the Claimed Dosage Range
The claims additionally encompass a daily dosage range extending from 20 mg/day through 420 mg/day, including embodiments reciting 280 mg/day, 350 mg/day, and 420 mg/day. The present specification provides only limited therapeutic guidance regarding administration of the highest claimed daily doses. Subsequently, clinical development of PCLX-001 (zelenirstat) illustrates the amount of experimentation required to determine clinically tolerable therapeutic dosing.
Specifically, Sangha et al. (Investigational New Drugs (2024) 42:386–393) conducted a first-in-human Phase I dose-escalation study involving twenty-nine patients receiving daily doses ranging from 20 mg/day through 280 mg/day. The investigators determined that gastrointestinal dose-limiting toxicities first occurred in the 200 mg/day, thereby establishing 210 mg/day as both maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D). (Abstract.) Thus, substantial additional clinical experimentation was required to determine that administration above 210 mg/day resulted in dose-limiting toxicities. The present specification provides insufficient guidance demonstrating that the highest claimed daily doses (280 mg/day, 350 mg/day, and 420 mg/day) may safely and effectively administered to achieve the claimed therapeutic methods.
Accordingly, one of ordinary skill in the art would be required to undertake substantial additional clinical investigation to determine whether the highest claimed daily doses constitute operable therapeutic embodiments.
IV. Predictability of the Art
The art of oncology is highly unpredictable. Lovly et al. (Am Soc Clin Oncol Educ Book. 2016; 35: e585-e593) explained that tumor heterogeneity encompasses both intertumor and intratumor heterogeneity that that tumors sharing the same histopathology diagnosis frequently differ genetically, phenotypically, metabolically, proliferatively, and ultimately in therapeutic response. (See page 12.)
Lovly et al further explains that intertumor and intratumor heterogeneity represents significant obstacles in designing effective therapeutic strategies because treatment selected from one tumor sample may not produce responses throughout the tumor and there is not reliably method to predict tumor evolution over time. (See third paragraph of page 3.)
Moreover, Lovly et al. reports that even tumor sharing the same oncogenic driver frequently exhibit markedly different clinical response to the same targeted therapy. For example, BRAF-mutated melanoma responds favorably to selective BRAF inhibitors, whereas BRAF-mutated colorectal cancer rarely demonstrates comparable responses despite sharing the same molecular alteration. (See pages 2 and 4.)
Accordingly, one of ordinary skill in the art would not reasonably expect therapeutic efficacy demonstrated for one cancer type to predict efficacy for throughout the broad spectrum of unrelated malignancies encompassed by the claims.
V. Quantity of Experimentation Required
The amount of experimentation required to practice the full scope of the claimed invention would be substantial.
With respect to therapeutic scope, one of ordinary skill would be required to determine which of the numerous recited cancers respond therapeutically to PCLX-001, identify responsive patient populations, correlate molecular subtypes with therapeutic response, and establish clinical efficacy throughout the broad range of claimed malignancies.
With respect to the dosage scope, one of ordinary skill would further be required to determine whether the highest claimed daily dosage (280 mg/day, 350 mg/day, and 420 mg/day) may be safely and effectively administered notwithstanding subsequent evidence establishing dose-limiting toxicities at 280 mg/day and identifying 210 mg/day as the maximum tolerated dose. (See Abstract of Sangha et al.) Such experimentation would necessarily require extensive clinical investigation rather than routine optimization.
VI. Wands Factors
Considering the factors identified in in re Wands, the breadth of the claims, the limited number of therapeutic working examples, the limited therapeutic guidance provided by the specification, the highly unpredictable nature of oncology, and the substantial quantity of experimentation required to determine both therapeutic efficacy across the full scope of the claimed cancers, and the operability of the highest claimed dosage embodiments collectively establish that undue experimentation would be required.
Accordingly, the specification does not enable the full scope of the claimed invention as required by 35 U.S.C. 112(a).
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 1-19 and 22 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.
Independent claim 1 recites, in relevant part “… administering an oral dosage gorm of PCLX-001…” followed by “… wherein said oral dosage….” Thus, the claimed article being administered is expressly defined as an oral dosage form and further expressly defined as oral dosage.
However, the independent claim 1, dependent claims 2-18 no longer refer to the previously-recited oral dosage form, but instead recite limitations directed to an “oral dosage.” For example, claim 2 recites “wherein the oral dosage is administered ….” Similarly, the remaining dependent claims recite limitations directed to “oral dosage” rather than “the oral dosage form.” Accordingly, it is unclear whether the recited “oral dosage” is intended to refer to:
the previously-recited oral dosage form;
the amount of the drug administered;
an individual dosage unit;
a daily dosage;
a dosing regimen; or
some other subject distinct from the oral dosage form recited in claim 1.
Because the independent claim 1 and the dependent claims introduce the different term
“oral dosage” in place of the antecedent “oral dosage form,” the metes and bounds of the claims are not reasonably certain.
The issue is not merely one of missing antecedent basis. Rather, the dependent claim claims and the independent claim 1 substitute a different claim term (“oral dosage”) for the previously-recited claim limitation (“oral dosage form”). These terms are not facially identical and reasonably convey different meanings to one of ordinary skill in the pharmaceutical arts. For example, an “oral dosage form” ordinarily refers to the physical form of the pharmaceutical formulation (e.g., tablet, capsule, solution, suspension), whereas an “oral dosage” may reasonably refer to the quantity of the active ingredient administered or the dosing amount, Because if it unclear whether the limitation “oral dosage” are further limiting the dosage form recited in claim 1, or instead introducing a different limitation directed to dosage amount, the scope of the claim is uncertain.
The specification likewise does not provide a clear definition demonstrating that the terms “oral dosage” and “oral dosage form” are intended to by synonymous. Accordingly, one of ordinary skill in the art would not be reasonably apprised of the scope of the claimed subject matter.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-6, 19, and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sangha et al. (63rd ASH Annual Meeting Abstracts, Boold 138 (2021) 1364-1365). This reference is cited in the IDS filed on 06/17/2025.
Sangha expressly teaches a method for treating B-cell lymphomas in a human patient comprising administering a dose of 20 mg daily to said patient. (See Abstract.)
With respect to “wherein the T1/2….” limitations recited in claims 2, 3, 5, and 3. The recited “wherein” clause stating that wherein the oral dosage provides an effect comprising a terminal half-life of about X hours merely express the pharmacokinetic result obtained by performing the positively recited administration step and does not require an additional affirmative method step. See MPEP 2111.04. Alternatively, to the extent the clause is accorded patentable weight, the claimed pharmacokinetic property is an inherent characteristic of administering the expressly disclosed oral dosage of PCLX-001 to the disclosed patient population under the disclosed treatment protocol.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-19 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Beauchamp et al (Nature Communications (2020) 11:5348, pages 1-16) in view of Weickert et al. (802 Chemical Biology and Experimental Therapeutics, November 13, 2019) and William et al. (WO2020/128475 A1). All references are cited in the IDS filed 06/17/2025 and 06/24/2026.
Beauchamp teaches that daily orally administration of PCLX-001 as an NMT inhibitor in the amount of 20 mg/kg and 50 mg/kg reduced tumor size and tumor inhibition in B-cell lymphoma animal models. (See Abstract; page 9; and figure 9.)
Beauchamp does not expressly teach the doses claimed and a human subject. Beauchamp does not further teach the T1/2 values recited in the claims.
Weicker teaches oral pharmacokinetics, toxicology, body-surface-area scaling, preliminary maximum tolerated doses, oral bioavailability, plasma half-life, and extrapolation of efficacious animal doses to human dosing concluding that pharmacokinetic properties support once-daily oral administration and progression to first-in-human studies. (See Abstract.)
William contemplated for systemic treatment of multiple MYC addicted cancers using NMT inhibitors such as PCLX-001. (See Abstract and claim 32). William provides additional guidance regarding administration and dosage ranges by stating that when orally administered to humans, the NMT inhibitor for use in the present invention will generally be administered at an amount of between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day, for adult humans. The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. (See paragraph [0098] and [0099].)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to employ the teaching of Weickert when translating the successful oral lymphoma treatment disclosed by Beauchamp into a human therapeutic regimen. Beauchamp establishes that orally administered PCLX-001 demonstrates significant antitumor efficacy in multiple B-cell lymphoma xenograft models at daily oral doses of 20 mg/kg and 50 mg/kg. thereby establishing proof-of-concept that orally administered PCLX-001 is therapeutically effective for treatment of lymphoma.
However, Beauchamp does not address those efficacious animal doses should be translated into a clinically appropriate human dosing regimen. (See Abstract; page 9; and figure 9.) Weicker expressly addresses that issue by characterizing the oral pharmacokinetics, toxicology, body-surface-area scaling, preliminary maximum tolerated doses, oral bioavailability, plasma half-life, and extrapolation of efficacious animal doses to human dosing, concluding that pharmacokinetic properties support once-daily oral administration and progression to first-in-human studies. (See Abstract.)
Accordingly, a person of ordinary skill in the art would have been motivated to employ Weickert’s pharmacokinetic and toxicological teachings when translating the oral efficacious lymphoma treatment disclosed by Beauchamp into a human therapeutic regimen because optimization of dosage and pharmacokinetic properties during transition from successful animal studies to first-in-human administration represented a routine and predictable aspect of a pharmaceutical drug development.
Furthermore, William reinforces that NMT inhibitors, including PCLX-001 (claim 32), were contemplated for systemic treatment of multiple cancers by oral administration and expressly teaches human dosage ranges and that the appropriate dosage would vary depending upon the disease, patient, route of administration, according to well-known principle of medicine. (See paragraph [0098] and [0099].) Thus, William further supports the ordinary artisan’s expectation that oral administration of PCLX-001 would be adapted to human therapeutic dosing.
One of ordinary skill in the art would likewise have had a reasonable expectation of success in employing the combined teachings of Beauchamp, Weickert, and William. Beauchamp demonstrates that orally administered PCLX-001 produces significant antitumor efficacy in multiple B-cell lymphoma xenograft models and establishes that orally administered PCLX-001 possess therapeutic activity against lymphoma. Weicker further demonstrates that PCLX-001 possess favorable oral bioavailability, pharmacokinetic characteristics, plasma half-life, and a therapeutic window supporting once-daily oral administration while providing body-surface-area scaling and extrapolation of efficacious animal doses toward human dosing. William additionally teaches oral administration of NMT inhibitor for treatment of cancer in human subjects and provides dosages guidance for human administration, thereby reinforcing that translation of orally PCLX-001 from successful animal efficacy studies into human therapeutic use would have represented nothing more than the predictable application of known pharmacological principles to a known orally active anticancer compound. Accordingly, one of ordinary skill in the art would have reasonably expected that routine optimization of human oral dosage based upon known pharmacokinetics, toxicological, and dose-escalation principles would result in an effective once-daily oral dosing regimen for treatment of lymphoma.
Regarding the claimed daily dose of 20mg PCLX-001 per day, 40mg PCLX-001 per day, 70mg PCLX-001 per day, 100mg PCLX-001 per day, 140mg PCLX-001 per day, 210mg PCLX-001 per day, 280mg PCLX-001 per day, 350mg PCLX-001 per day, or 420mg PCLX-001 per day. Beauchamp establishes that orally administered PCLX-001 exhibits dose-dependent antitumor activity, while Weicker teaches body-surface-area scaling, pharmacokinetic characterization, oral bioavailability, and extrapolation of efficacious animal doses to human dosing. William further teaches broad human dosage ranges for orally administered NMT inhibitors and explains that the specific therapeutic dose depends upon the condition being treating and the patient, consistent with routine clinical dose optimization. Therefore, selection of the particular daily oral doses would have amounted to no more than routine optimization of result-effective variables, which is ordinary within the level of ordinary skill in the art. See in re Aller, 220 F.2d 454 (CCPA 1955) or in re Peterson, 315 F.3d 1825 (Fed. Cir. 2003). Optimization of dosage and other result-effective variables ordinarily falls within the routine skill of the art.
With respect to the dependent claims reciting terminal half-life (T1/2) values, the recited half-life values represent a pharmacokinetic property resulting from administration of the positively recited oral dosage regimen rather than an affirmative method step performed by the practitioner. See MPEP 2111.04. Alternatively, even if accorded patent weight, Weickert expressly teaches determination of oral pharmacokinetic parameters, including plasma half-life, as an integral part of developing orally administered PCLX-001 for human therapeutic use. A person of ordinary skill in the art would have routinely characterized the pharmacokinetic profile of the selected oral dosage regimen, and the resulting half-life values would have represented inherent pharmacokinetic properties of administering the selected oral doses rather than a separate inventive feature.
Conclusion
Claims 1-19 and 22 are not allowed.
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.
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, Amy L Clark can be reached at 571-272-1310. 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.
/JEAN P CORNET/ Primary Examiner, Art Unit 1628
Prosecution Insights