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
This office action is a response to Applicant’s amendments/remarks after non-final rejection filed 11/4/2025.
As filed, claims 1-9, 11, 12, 14, 17, 21-24, 27, 28, and 30 are pending; and claims 10, 13, 15, 16, 18-20, 25, 26, and 29 are cancelled.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/4/2025 has been considered by the Examiner.
Drawings
The drawings of Figs. 21, 23-25, and 27 were received on 11/4/2025. These drawings are acceptable.
Response to Amendments/Remarks
Applicant’s amendments/remarks, filed 11/4/2025, with respect to claims 1-9, 11, 12, 14, 17, 21-24, 27, 28, and 30, have been fully considered and are entered. The status for each rejection in the previous Office Action is set out below.
The § 112(a) scope of enablement rejection of claims 12, 14, 17, 21-24, 27, 28, and 30 is maintained. The amendments in claims 12 and 24, which incorporated the phrase, -- wherein the method is a method of treatment --, at the end of the claims did not exclude the prophylactic language in “treating” because the specification defines “treating” or “treatment” to include preventing (see snapshot below). Accordingly, the 112(a) scope of enablement rejection is maintained. To overcome the rejection, amend the following:
the phrases in claim 12, “or susceptible to” and “, wherein the method is a method of treatment” need to be removed;
the phrase in claim 24, “in need thereof”, needs to be replaced with – having said cancer or tumors --; and
the phrase in claim 24, “, wherein the method is a method of treatment”, need to be removed.
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(pg. 6, lines 2-8)
The § 112(a) scope of enablement rejection of claims 8, 9, and 11 is withdrawn per amendments.
The § 112(b) indefinite rejection of claims 27 and 28 is withdrawn per amendments.
The claim objection of claims 8 and 17 is withdrawn per amendments.
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 12, 14, 17, 21-24, 27, 28, and 30 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 therapeutically treating a subject susceptible to a cell proliferation related disorder or disease (e.g. cancer or tumor), does not reasonably provide enablement for prophylactically treating (i.e. preventing) a subject susceptible to a cell proliferation related disorder or disease. 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 and/or use 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 (Fed. Cir. 1988)), the Federal Circuit established that the following factors are to be considered when determining whether a disclosure meets the enablement requirement of the first paragraph of 35 U.S.C. § 112:
The nature of the invention - is a method of treating a subject susceptible to a cell proliferation related disorder or disease via a compound of instant formula (I). In addition, the term, “treating”, not only embrace for therapeutic treatment but also for prophylaxis (instant specification, pg. 6, lines 2-8).
The state of the prior art - the pharmacological art requires the screening of potential drug candidates in vitro and in vivo to determine if the drug candidates exhibit the desired pharmacological activities.
In order to treat a disease: one would need to precisely identify what the disease is, identify what biological target is connected with the disease, demonstrate that the drug candidate in some way modulates the normal processes of the biological target, and demonstrate that a patient benefited from such modification without detrimental side effects. Typically, this process includes in vitro laboratory screening, preclinical in vivo screening, and three phases of clinical trials. Once this arduous process has been successfully completed by a drug candidate, subsequent drug candidates will benefit from the established proof of concept. The subsequent drug candidates must demonstrate a substantial correlation between their biological activity and that of the known drug candidate.
In order to prevent a disease: one would need to precisely identify those subjects likely to acquire such a disease, administer Applicant’s claimed invention, and demonstrate that the patient did not develop the disease as a result of the administration of the claim invention.
In the instant case, the prior arts recognize that small molecule therapeutic agents and macrocyclic depsipeptides have potential to destabilize microtubule, which can be used to treat a number of diseases, such as cancer, etc. See Weiss et al., Cryptophycins: cytotoxic cyclodepsipeptides with potential for tumor targeting. Journal of Peptide Science, 2017, 23, pg. 514-531; and Prota et al., The Novel Microtubule-Destabilizing Drug BAL27862 Binds to the Colchicine Site of Tubulin with Distinct Effects on Microtubule Organization. Journal of Molecular Biology, 2014, 426, pg. 1848-1860 (see PTO-892 form mailed on 8/4/2025).
The predictability or unpredictability of the art – the law recognizes the pharmaceutical art as an unpredictable art and requires each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970). Accordingly, the more unpredictable an area is the more specific disclosure is necessary in order to satisfy the statute. Section 2164.02 of the MPEP provides:
"[C]orrelation” as used herein refers to the relationship between in vitro and in
vivo animal model assays and a disclosed or a claimed method of use . . . if the
art is such that a particular model is recognized as correlating to a specific
condition, then it should be accepted as correlating unless the examiner has
evidence that the model does not correlate.
In light of these remarks, the Examiner finds that one of ordinary skill in the art would agree with the court; that is, the pharmaceutical art is unpredictable. Thus, a substantial correlation is necessary for establishing the potential of new therapeutics.
The amount of direction or guidance presented – the instant specification briefly provides an explanation of the biological activity of microtubules on pp. 1 that discuss the implication of microtubules-destabilizing agent in the treatment of the abovementioned disorder or disease. There is no direction or guidance provided that supports a use of microtubules-destabilizing agent as a drug for preventing the abovementioned disorder or disease, as instantly embraced.
The amount of guidance or direction to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. MPEP § 2164.03 (quoting In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970)). As identified supra, the pharmaceutical art is recognized as unpredictable.
Thus, in order to support a claim for preventing the abovementioned disorder or disease, a vast amount of evidence is required because such a claim is not supported by the prior art or the instant specification.
The presence or absence of working examples - there are no working or prophetic examples in the specification that demonstrate that the instant compounds or composition thereof may prevent the abovementioned disorder or disease, as instantly embraced. The assays in the specification demonstrate that the instant compounds were tested for their ability to inhibit tubulin polymerization in vitro and for their cytotoxicity toward cancer cells (pg. 51-54 of the instant specification)
The breadth of the claims – is incommensurate in scope with the disclosure because a fair reading of the specification fails to support a finding that the compounds of instant formula (I) may prophylactically treating (i.e.prevent) the abovementioned disorder or disease in a patient.
The quantity of experimentation necessary – generally speaking, the amount of experimentation to transform a molecule into medicine is vast and the success thereof is low. Recent statistics indicate that the attrition rates during drug development remain high. Schafer et al. Drug Discovery Today 2008, 13 (21/22), 913-916 (see PTO-892 form mailed on 8/4/2025). The article makes clear that there are many steps necessary to promote a new molecular entity toward its clinical use, any one of which is cumbersome.
For instance, Schafer et al. discloses: "proof of concept trials have failed when the decision to enter clinical development was based on preclinical experiments using the wrong compound, the wrong experimental model, or the wrong endpoint.” It can be gleaned from this article that a plethora of experimentation is needed to identify the lead compound (i.e. one among many in a Markush-type claim), to establish which preclinical tests are predictive of clinical success, and to establish which diseases are the best to target for each lead compound.
There is generally a vast amount of experimentation to take a drug from bench to the clinic. See e.g., Horig et al. Journal of Translational Medicine 2004, 2(44) (see PTO-892 form mailed on 8/4/2025) (“Successful drug development requires satisfying a matrix of domains from relevance to the disease and the drug-ability of the target through feasibility and convenience of drug delivery, demonstration of favorable benefit-risk profile in order to achieve a drug label that reflects physician and patent acceptance.") The Examiner finds that one of ordinary skill in the art would agree with the statements in these articles; that is, the amount of experimentation required to enable a pharmaceutical drug is extensive.
The level of skill in the art - the level of ordinary skill in the art may be found by inquiring into: (1) the type of problems encountered in the art; (2) prior art solutions to those problems; (3) the rapidity with which innovations are made; (4) the sophistication of the technology; and (5) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of those factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983).
Based on the typical education level of the active workers in the field of pharmaceuticals and/or medicine, as well as the high degree of sophistication required to solve problems encountered in the art, the Examiner finds that a person of ordinary skill in the art would have at least a college degree in a field related to medicine and/or the pharmaceutical art and at least four years of work experience, i.e. a masters or doctorate level scientist/clinician.
Conclusion – Claims 12, 14, 17, 21-24, 27, 28, and 30 are rejected because the Examiner finds that the Wands factors suggest a conclusion that the skilled artisan would not be able to make and use the instant invention without undue experimentation, although the level of skill for an ordinary person in the art is high. That is, due to the breadth of the claims, the unpredictability of the art, the lack of guidance or direction from the disclosure, the lack of any working examples, and the amount of experimentation needed illustrate that a person having ordinary skill in the art would not be able to prophylactically treating (i.e. prevent) a subject susceptible to a cell proliferation related disorder or disease (e.g. cancer or tumor).
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 11 is 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 11, the claim is dependent of claim 8, and claim 11 recites the phrase, “the modulation” wherein the word, “the”, requires antecedent basis, and it is unclear where applicant has defined “a” modulation in claim 8 or 11. Without antecedent basis, the claim is rendered indefinite.
Claim Rejections - 35 USC § 112 fourth paragraph
The following is a quotation of the fourth paragraph of 35 U.S.C. § 112:
Subject to the following paragraph [concerning multiple dependent claims], 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 (emphasis added).
Claim 11 is rejected under the fourth paragraph of 35 U.S.C. § 112 and under 37 CFR § 1.75(c), as being of improper dependent form for failing to further limit the subject matter of a previous claim. Applicant is required to cancel the claim(s), or amend the claim(s) to place the claim(s) in proper dependent form, or rewrite the claim(s) in independent form.
Regarding claim 11, the claim is dependent upon claim 8. The subject matter in claim 8 is drawn to a process of reducing and/or halting cell proliferation via a compound of instant formula (I). The subject matter in claim 11 is drawn to a limited embodiment of the abovementioned process.
The scope of claim 11 is broader than scope of claim 8 because claim 11 includes subject matter that are outside of claim 8 (e.g. modulation, wherein the modulation is inhibition, are both absent in claim 8). Because the scope of claim 11 is broader than claim 8, the claim failed to further limit the subject matter thereof, and fail to comply with the formal requirements set forth in the fourth paragraph of 35 U.S.C § 112.
The Examiner suggests that the claims be amended in a manner such that the scope of claim 11 is commensurate with the scope of claim 8.
Allowable Subject Matter
Claims 1-9 are allowed.
Conclusion
Claims 11, 12, 14, 17, 21-24, 27, 28, and 30 are rejected.
Claims 1-9 are allowed.
Claims 10, 13, 15, 16, 18-20, 25, 26, and 29 are cancelled.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Telephone Inquiry
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PO-CHIH CHEN whose telephone number is (571)270-7243. The examiner can normally be reached Monday - Friday 10:00 am to 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571)270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PO-CHIH CHEN/Primary Examiner, Art Unit 1621