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 .
Status of the Claims
Claims 1-13, 15, 21, 23, and 27 are pending.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Instant application is a U.S. National Stage Entry of PCT/EP2022/062061, filed 05/04/2022. PCT/EP2022/062061 claims priority of foreign application CN202210409814.5, filed 04/19/2022. Therefore, the effective filing date is 04/19/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/16/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Objection – Drawings
37 C.F.R. 1.84:
(p) Numbers, letters, and reference characters.
(1) Reference characters (numerals are preferred), sheet numbers, and view numbers must be plain and legible, and must not be used in association with brackets or inverted commas, or enclosed within outlines, e.g., encircled. They must be oriented in the same direction as the view so as to avoid having to rotate the sheet. Reference characters should be arranged to follow the profile of the object depicted.
(u) Numbering of views.
(1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.
(2) Numbers and letters identifying the views must be simple and clear and must not be used in association with brackets, circles, or inverted commas. The view numbers must be larger than the numbers used for reference characters.
The drawings are objected to because the views numbers are not preceded by “FIG.”, the view heading is oriented in a different direction than the view itself, and the view numbers are not larger than the reference characters in some views (e.g., FIG. 6A-8 and 10).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 1-4, 9-13, 15, 21, 23, and 27 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 crystalline form of Formula I or an adduct thereof with one or more lysine molecules, does not reasonably provide enablement for any adduct with a crystalline form of Formula I. 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 the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention
The nature of the invention relates to crystalline compounds of Formula I and adducts thereof in claim 1. Such compounds are useful for the treatment of specific cancers and multiple sclerosis. This invention is also directed to compositions and methods comprising said compounds.
Predictability of the art
The compounds synthesized in the instant specification appear novel. However, the hypothetical compounds in claim 1 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 1. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
4. The breadth of the claims
The scope of the claims involves crystalline forms of Formula I and adducts thereof, shown below.
PNG
media_image1.png
139
280
media_image1.png
Greyscale
Claim 1 is indefinite in the number of variables and the options of substituents for each variable. There is an indefinite amount of hypothetical compounds included in claim 1, due to the undefined term “adduct”.
5. The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary
The specification only provides the synthesis of a crystalline form of Formula I, and adducts of Formula I with one or two L-lysine molecules.
Synthesis methods are not taught in the specification to provide for the indefinite amount of potential adducts of Formula I, which the specification teaches also includes “non-pharmaceutically acceptable adducts” (page 7). Additionally, no in vitro complex with HDAC6 is synthesized in the specification. It would require one skilled in the art, such as a chemist, to perform an indefinite number of reactions to determine which of the adducts of Formula I can be prepared that would read on the instant claims and would require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claims 21 and 23 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 treating mantle cell lymphoma, lung cancer, pancreatic cancer, and multiple sclerosis comprising administering the crystalline form of Formula I or an adduct of Formula I with one or more lysine molecules, does not reasonably provide enablement for the treatment of any proliferative or autoimmune disease comprising administering a compound of Formula I or adduct thereof. 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.
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. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the present invention, are summarized as follows:
Breadth of the claims
The breadth of the claim includes a method of treating a proliferative or autoimmune disease in a patient, comprising administering a compound of the Formula I or adduct thereof.
Nature of the invention
The nature of the invention is performance of a method of treating a proliferative or autoimmune disease in a patient, comprising administering a compound of Formula I or adduct thereof.
State of the prior art
No single drug has been discovered that is effective in treating the myriad of proliferative and autoimmune diseases in a patient, including, but not limited to, breast cancer, chronic myelogenous (or myeloid) leukaemia (CML), colorectal cancer, lymphoma (such as non-Hodgkin lymphoma), fibrosarcoma, gastric cancer, glioblastoma, kidney cancer, liver cancer, lung cancer, melanoma, nasopharyngeal cancer, oral cancer, orthotopic multiple myeloma, osteosarcoma, ovarian cancer, pancreatic cancer, and prostate cancer, autoimmune hepatitis; an
inflammatory demyelinating disease of the central nervous system; systemic lupus erythematosus; acute anterior uveitis; Sjogren's syndrome; rheumatoid arthritis; diabetes35 meitus type 1; Graves' disease; and inflammatory bowel disease, multiple sclerosis (MS), including relapsing-onset MS, progressive-onset MS, optic-spinal MS; neuromyelitis optica; acute-disseminated encephalomyelitis; acute haemorrhagic leukoencephalitis; Balo concentric sclerosis; Schilder's disease; Marburg MS; tumefactive MS; solitary sclerosis; optic neuritis; transverse myelitis; Susac's syndrome; leukoaraiosis; myalgic encephalomyelitis; Guillain-Barre syndrome; progressive inflammatory neuropathy; leukodystrophy, including adrenoleukodystrophy and adrenomyeloneuropathy (specification, pages 21-22). See In re Hokum, 226 USPQ 353 (ComrPats 1985).
The prior art teaches the treatment of mantle cell lymphoma, lung cancer, pancreatic cancer, and multiple sclerosis comprising administering QTX125 (WO 2018087082 A1; Perez-Salvia et al., In vitro and in vivo activity of a new small-molecule inhibitor of HDAC6 in mantle cell lymphoma, Haematologica, 2018, Vol. 103(11), pages e537-e540). Therefore, Applicant would be enabled for the treatment of these diseases.
Level of one of ordinary skill in the art
The artisans performing the inventor’s or joint inventor’s method of treating a proliferative or autoimmune disease in a patient, comprising administering a compound of Formula I or adduct thereof, would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
Level of predictability in the art
Synthetic organic chemistry is quite unpredictable. See In re Marzocchi and Horton 169 USPQ at 367 ¶3. Similarly, it is well established that “[T]he scope of enablement varies inversely with the degree of unpredictability of the factors involved, and physiological activity is generally considered to be an unpredictable factor”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The nature of the invention and predictability in the art, with specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] ...anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”.
Amount of direction provided by the inventor
The invention lacks direction with respect to making and/or using (performing) a method of treating a proliferative or autoimmune disease in a patient, comprising administering a compound of Formula I or adduct thereof.
Existence of working examples
The disclosure is insufficient to allow extrapolation of the limited examples to enable performing the instantly recited method of treating a proliferative or autoimmune disease in a patient, comprising administering a compound of Formula I or adduct thereof.
Similarly, according to the specification, compounds of Formula I or adducts thereof are capable of treating a variety of proliferative and autoimmune diseases in a patient, including, but not limited to, the above listed diseases found in the specification (pages 21-22).
However, the specification fails to set forth any in vitro and/or in vivo assays corroborating the alleged activity in association with any of the aforementioned diseases. The specification provides no examples for the treatment of any disease comprising administering a compound of Formula I or adduct thereof. There is insufficient disclosure to reasonably conclude that the method of treating a proliferative and autoimmune disease in a patient, comprising administering a compound of Formula I or adduct thereof, as recited, would contribute to treatment of any the aforementioned diseases. Additionally, the specification teaches, on page 7, that the adducts include “non-pharmaceutically acceptable adducts”, which would not be expected to be useful in the treatment of any disease. The inventor or joint inventor has neither provided convincing data for any patient population, nor indicated any art recognized correlation between the disclosed data and the breadth of the claim.
Quantity of experimentation needed
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use (perform) the full scope of the claimed invention without undue experimentation. See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
One skilled in the art, such as a medical doctor, would be required to perform hundreds or thousands of clinical trials and in vivo or in vitro assays in order to determine which of the compounds and adducts of Formula I would be capable of treating which proliferative and autoimmune diseases. Even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404. These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on the evidence presented herein, the conclusion that the inventor is insufficiently enabled for a method of treating a proliferative and autoimmune disease in a patient, comprising administering a compound of Formula I or adduct thereof, is clearly justified.
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 1-5, 9-13, 15, 21, 23, and 27 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.
Regarding claim 5, the phrase "Form 2" renders the claim indefinite because “Form 2” is not defined, thereby rendering the scope of the claim and unascertainable.
Regarding claims 1-4, 9-13, 15, 21, 23, and 27, the phrase “adduct” render the claims indefinite because the claims include elements not actually disclosed (those encompassed by "adduct"), thereby rendering the scope of the claims unascertainable. The specification, on page 7, defined “adduct” as “a product of a direct addition of two or more distinct molecules”. The specification also teaches that “non-pharmaceutically acceptable adducts also fall within the scope of the invention”. Therefore, only non-limiting definitions of “adduct” are taught in the specification, resulting in an indefinite number of “adducts” encompassed by the instant claims.
Advisory Notice
Claims 6-8 appear allowable if rewritten in independent form.
Conclusion
Claims 1-5, 9-13, 15, 21, 23, and 27 are rejected.
Claims 6-8 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RILLA M SAMSELL whose telephone number is (703)756-5841. The examiner can normally be reached Monday-Friday, 7-3.
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, Jeffrey Murray can be reached at (571) 272-9023. 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.
/R.M.S./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
Prosecution Insights