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 .
DETAIL ACTION
This office action is a response to a 371 application filed -----11/10/2023, which is a national stage application of PCT/US2022/028759 filed 5/11/2022, which claims domestic priority to 63/187,297 filed 5/11/2021.
As filed, claims 1-11 are pending, wherein claims 1, 6, and 8 are independent claims.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/10/2023; 10/14/2024; and 4/29/2025 has been considered by the Examiner.
Priority
The instant application is a 371 (i.e. national stage) application of PCT/US2022/028759 filed 5/11/2022, which claims the benefit under 35 USC 119 (e) from US Provisional Applications 63/187,297 filed 5/11/2021.
With respect to the claim for the benefit of an effective U.S. filing date, it is noted that “the written description and drawing(s) (if any) of the provisional application must adequately support and enable the subject matter claimed in the nonprovisional application that claims the benefit of the provisional application. In New Railhead Mfg., L.L.C. v. Vermeer Mfg. Co., 298 F.3d 1290, 1294, 63 USPQ2d 1843, 1846 (Fed. Cir. 2002), the court held that for a nonprovisional application to be afforded the priority date of the provisional application, 'the specification of the provisional must contain a written description of the invention and the manner and process of making and using it, in such full, clear, concise, and exact terms' to enable an ordinarily skilled artisan to practice the invention claimed in the nonprovisional application" [MPEP 201.11A - emphasis in original].
It is noted that the requirement for support is evaluated for each claim individually such that different claims may be examined with different effective filing dates. In the instant case, the ‘297 provisional application did not provided support for the entire scope of the compound of instant formula (I) (e.g. instant variables R1 and R2 are other than H and R4 is OH) and/or the process of making the compound of instant of formula (I). Accordingly, the instant compounds, wherein as shown in claims 1 and 5-11 are examined with an effective filing date of 5/11/2022 (the filing date of the PCT application; i.e. earliest filing date) because the instant compounds, wherein the compound has instant variables R1 and R2 are other than H and R4 is OH, and/or the process of making the compounds thereof, as shown in claims 1, 5, and 6, are not disclosed and supported by the ’297 provisional application. As for instant compounds depicted in claims 2-4, they are examined with an effective filing date of 5/11/2021 (the filing date of the ‘297 provisional application) because the instant compounds depicted in claims 2-4 are fully supported by the ‘297 provisional application.
Should applicant desire that the benefit of an earlier effective filing date be according any of the instant claims, the claims must be amended such that they are fully supported by the ‘656 provisional application.
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 8-11 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 glioblastoma, does not reasonably provide enablement for treating any cancer or for inhibiting protein synthesis through interactions with peptidyl transferase center of a ribosome. 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 any cancer or a method of inhibiting protein synthesis through interactions with peptidyl transferase center of a ribosome via a compound of instant formula (I).
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 the instant case, the prior art recognizes that agelastatin A can treat cancer by inhibiting protein synthesis through interactions with peptidyl transferase center of a ribosome. However, the prior art failed to demonstrate that 7-hydroxy agelastatin A (i.e. compound of instant formula I) have any cytotoxicity against cancer or can inhibit protein synthesis through interactions with peptidyl transferase center of a ribosome. More importantly, Applicant’s own work (see Cite No. 5 in IDS filed 11/10/2023) only demonstrated that 7-hydroxy-13-des-bromo agelastatin A, which shares the same core structure as the instant compounds, has cytotoxicity against glioblastoma.
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 agelastatin A on pp. 1-2, in the treatment of cancer or its ability to bind to peptidyl transfer center of the ribosome which leads to protein synthesis inhibition. There is no direction or guidance provided that supports a use of the 7-hydroxy agelastatin A (i.e. compound of instant formula I) for treating any cancer or for inhibiting protein synthesis through interactions with peptidyl transferase center of a ribosome, 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 treating any cancer, 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 treat any cancer or for inhibiting protein synthesis through interactions with peptidyl transferase center of a ribosome, as instantly embraced. The assays in the specification only demonstrate that 7-hydroxy-13-desbromo agelastatin A (which share the same core structure as the instant compounds) was tested for their cytotoxicity against cell lines of breast cancer, colon cancer, and glioblastoma (pg. 38 and fig. 10 of the instant specification), and 7-hydroxy-13-desbromo agelastatin A is only active against glioblastoma.
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 treat any cancer or may inhibit protein synthesis through interactions with peptidyl transferase center of a ribosome 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. 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) (“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 8-11 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 treat any cancer outside of glioblastoma or to inhibit protein synthesis through interactions with peptidyl transferase center of a ribosome.
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 10 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 10, the claim recites the phrase, “the peptidyl transferase center in a subject” wherein the word, “the”, requires antecedent basis, and it is unclear where applicant has defined “a” peptidyl transferase center in a subject. 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).
Claims 4 and 5 are 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 4, the claim is dependent upon claim 1. The subject matter in claim 1 is drawn to a compound of instant formula (I). The subject matter in claim 4 is drawn to a limited embodiment of instant formula (I).
The scope of claim 4 is broader than scope of claim 1 because claim 4 includes species that are outside of instant formula (I) (e.g. R3 is H). Because the scope of claim 4 is broader than claim 1, 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 4 is commensurate with the scope of claim 1.
Regarding claim 5, the claim is dependent upon claim 1. The subject matter in claim 1 is drawn to a compound of instant formula (I). The subject matter in claim 5 is drawn to a limited embodiment of instant formula (I).
The scope of claim 5 is broader than scope of claim 1 because claim 5 includes species that are outside of instant formula (I) (e.g. R1 and R2 include halogens outside of F, Cl, and Br; and R3 is H). Because the scope of claim 5 is broader than claim 1, 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 5 is commensurate with the scope of claim 1.
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.
Claims 1 and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by “Synthesis of agelastatin A and derivatives premised on a hidden symmetry element leading to analogs displaying anticancer activity”, hereinafter Xue. See IDS filed 11/10/2023.
Regarding claims 1 and 5, Xue, for instance, teaches the following compounds, which meet all the limitations of these claims.
For claim 1:
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306
280
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(pg. 2, Fig. 1, 7-hydroxy agelastatin A, 7a)
For claim 5:
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220
179
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(pg. 4, Scheme 3, compound 24)
Wherein instant variables R1 and R2 are H; instant variable R3 is H or Br; and instant variables R4 and R5 are H.
Claim Objections
Claims 6 and 10 are objected to because of the following informalities:
Regarding claim 6, the claim recites the phrase, “converting 7-hydroxy compound (b) to the compound of formula (I) by treatment aqueous acid”.
Such expression can be clarified by reciting -- converting 7-hydroxy compound (b) to the compound of formula (I) by treatment of aqueous acid --.
Regarding claim 10, the claim recites the phrase:
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168
650
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Wherein the phrase at the end of the claim, “in an amount effective to inhibit protein synthesis through interactions with the peptidyl transferase center of a ribosome”, is redundant and thus, can be removed.
Appropriate correction is required.
Allowable Subject Matter
Claims 2, 3, and 7 are objected to as being dependent upon 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.
Conclusion
Claims 1, 4, 5, and 8-11 are rejected.
Claims 2, 3, 6, 7, and 10 are objected.
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