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
Claims 1-14 are currently pending in the application.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. The earliest application that provides adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application is the provisional application 63/292,766. Thus, the priority date of the instant invention is December 22nd, 2021.
IDS
The information disclosure statement (IDS) submitted 06/20/24, 12/19/25, and 04/13/26 are acknowledged and have been entered. The submission is in compliance with the provisions of 37 CFR 1.97. However, Foreign Patent AU 2018 373 053 was not considered as the document was not provided. Accordingly, the information disclosure statements have been considered by the examiner.
Objections
Claim 10 is objected to because of the following informalities: Line 8 should recite “the effective amount” of “”a”” composition…. In addition, claim 12, should recite “cancer” instead of “caner”. Appropriate correction is required.
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 waspointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
"The primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent. A secondary purpose is to provide a clear measure of what applicant(s) regard as the invention so that it can be determined whether the claimed invention meets all the criteria for patentability and whether the specification meets the criteria of 35 U.S.C. 112, first paragraph with respect to the claimed invention.", (see MPEP § 2173).
Claims 1 and 10-14 are rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Specifically, claim 1 recites a method of treating or preventing tumor recurrence or metastasis, comprising administering a pharmaceutically effective amount of a bedaquiline derivative with a TPP moiety. In the specification in paragraph 0040, derivative is defined as a chemical moiety derived or synthesized from a referenced chemical moiety wherein a bedaquiline derivative has a conjugated TPP moiety attached at the dimethyl amino end or at the bromine position. Such definition failed to specifically establish what part of the bedaquiline needs to remain as a derivative other than the dimethyl amino or bromine part of the bedaquiline. As a result, one skilled in the art would not be apprised of what constitute a true derivative of bedaquiline as the metes and bounds of the claim is not clearly delineated.
In addition claims 11 and 13 recite specific definition for m, n, A, and X but yet failed to recite a specific generic formula. Consequently, it is unclear what these particular moiety definitions are actually defining with no specific recitation of a generic compound.
Also, with respect to claim 10, “the level” of biomarkers is recited but the specification failed to recite what particular level is applicant expecting to achieve. Consequently, such recitation lacks antecedent basis.
As a result of the above inconsistencies, the aforementioned claims are unable to be examined as disclosed given that the scope of the claimed subject matter would not be able to be determined by one of ordinary skill in the art. For the sake of compact prosecution, the examiner will construe that the term “derivative” means that the core structure of bedaquiline needs to be present for the compound to be construed as a bedaquiline derivative.
Claim Rejections - 35 USC § 112 – 1st Paragraph, Written Description
The following is a quotation of the first paragraph of 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 1-3, 6, and 9-14 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection, rather than an enablement rejection under 35 U.S.C. 112, first paragraph. Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1st "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
The claims are drawn to a method for treating or preventing at least one of tumor recurrence and metastasis in a subject, comprising administering a pharmaceutically effective amount of a bedaquiline derivative with a TPP moiety.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, states that Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117).
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, "An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention."
As defined in paragraph 40 of the specification and delineated in paragraph 12, Bedaquiline and derivatives of Bedaquiline are able to induce ATP-depletion in cancer cells and which was sufficient to prevent the onset of metastasis by targeting ATP5F1C, the gamma subunit of the mitochondrial ATP-synthase (see paragraph 12). Importantly, the specification only teaches and tested two specific bedaquiline derivatives that have the following general structure:
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478
1033
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(compound 2B above) and compound 3B below:
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942
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Per the definition for derivatives, bedaquiline derivatives encompass, for example, any compound that is derived or synthesized from bedaquiline. According to such definition a compound which solely contains a naphthyl group, a dimethyl amino group, or quinoline moiety and which further contain a TPP moiety (i.e. 3 phenyl groups attached to a phosphorus) would be considered a derivative of bedaquiline and would thus be encompassed by claim 1. Yet, the specification only tested or recite two derivatives. Consequently, the claims encompass numerous species, ranging from a compound as simple a dialkyl amino with a TPP moiety to quinoline moieties with a TPP attachment.
In addition, claims 2-3 recite the addition of moieties A & B in a generic compound wherein said moieties may be present or absent but yet the specification recites only 2 species that are derivatives of bedaquiline wherein A and B are both present and wherein such species fall within the scope of the claimed genus (see claims 4-5 or similar claims 7-8). The disclosure however fails to provide support for species wherein A and B are absent and thus the present claims encompasses numerous species that are not further described.
All of the disclosed species are very closely related to the core structure of bedaquiline and there is no evidence of record of other species that are structurally representative of the broadly claimed genus in claims 2 or 3 other than compound 2B and compound 3B. For example, the disclosed species is limited to m equals to 5 or 11; n equals to 4; and wherein A is O. As a result, the genus as disclosed is very limited in scope.
As discussed in the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1st “Written Description” Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001 (“the Written Description Guidelines”), the examination of patent claims for compliance with the Written Description Requirement should include:
1. A determination as to what the claim as a whole covers
2. A full review of the application to understand how the applicant provides support for the claimed invention including each element and/or step
3. A determination as to whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing. This determination should include the following considerations:
a. Actual reduction to practice
b. Disclosure of drawings or structural chemical formula
c. Sufficient relevant identifying characteristics, such as:
i. Complete structure
ii. Partial structure
iii. Physical and/or chemical properties
iv. Functional characteristics when coupled with a known or disclosed correlation between function and structure
d. Method of making the claimed invention
e. Level of skill and knowledge in the art
f. Predictability in the art
4. For each claim drawn to a single embodiment of species, consider the above factors in regard to that embodiment or species to determine whether one of ordinary skill in the art would recognize that the applicant was in possession of the species or embodiment at the time of filing
5. For each claim drawn to a genus, consider the above factors to determine whether there is disclosure of a representative number of species which would lead one skilled in the art to conclude that the applicant was in possession of the claimed invention. The number of species required to represent a genus will vary, depending on the level of skill and knowledge in the art and variability among the claimed genus. For instance, fewer species will be required where the skill and knowledge in the art is high, and more species will be required where the claimed genus is highly variable.
As to (1) above, the claims encompass any compound that is a chemical moiety that is derived or synthesized from bedaquiline, which is a genus encompassing millions of possible species. As discussed above, the specification discloses 21 structurally related species that are limited in scope to a very limited number of closely related compounds having the same substituents thereon.
As to (2) above, Applicants provide support for the claimed compounds by disclosure of a general formula and 2 specific species that fall within the scope of claims 2-3.
As to (3) above, the Specification only discloses two possible species encompassed by the aforementioned generic formula in claims 2-3. Actual reduction to practice is limited to a couple of species. The only relevant identifying characteristic disclosed in the Specification for the claimed compounds is the broadly described genus delineated in claims 2-3, 6, and 9. The Specification does not disclose any methods of making said compounds of the generic Formula.
In view of the above, the skilled artisan would not recognize that Applicants were in possession of the broad scope of the claimed compounds encompassed by the general formula, let alone treating cancer in patients with such compounds.
As to (5) above, the genus in the instant case is the claimed genus of the generic formula of claims 2-3. This genus is clearly "highly variable", encompassing any and all compounds that fall within the scope of the described Formula. As discussed above, this genus encompasses the aforementioned species, which are clearly highly variable.
Applicant’s disclosure of 2 species that appear to fall within the scope of the generic Formula as listed in paragraphs 0073 and 0075.
In view of the above, the Specification does not provide written support for the vast scope of compounds encompassed by the generic formula as presently claimed.
The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 112
Notice of AIA Status
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.
Claims 1-3 and 10-14 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 an individual with cancer; and while enabling for reducing the likelihood of tumor recurrence and metastasis by administering compound 2B and compound 3B, does not reasonably provide enablement for preventing tumor recurrence and metastasis comprising administering the generic compound of the formula delineated in claims 2-3 and 7-8. 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 instant claims are drawn to a method for treating cancer or reducing the likelihood of at least one of tumor recurrence and metastasis comprising administering an effective amount of a bedaquiline derivative with TPP moiety. The instant specification fails to provide information that would allow the skilled artisan to practice the prevention of tumor recurrence and metastasis comprising administering a bedaquiline derivative with TPP moiety.
[In re Sichert, 196 USPQ 209 (CCPA 1977)]
To be enabling, the specification of the patent 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 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
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 the 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).1
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 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:
1. The nature of the invention, state and predictability of the art, and relative
skill level
The invention relates to a method for treating cancer or reducing the likelihood of at least one of tumor recurrence and metastasis comprising administering an effective amount of a bedaquiline derivative with TPP moiety. The relative skill of those in the art is high, that of an MD or PHD. That factor is outweighed, however, by the unpredictable nature of the art. The specification (paragraph 0057) teaches that bedaquiline and compound 2B and compound 3B were effective in decreasing ATP production by downregulating ATP5FTC1. As illustrative of the state of the art, the examiner cites the fact that the specification in figure 5B demonstrated that inhibition ATP5F1C did not eradicate or prevent migration but rather reduced migration thereby supporting the notion that inhibitors of ATP production such as bedaquiline and by extension derivatives compound 2B and compound 3B would also be effective in reducing migration of cancer cells. Moreover, the CAM assay conducted in figure 12 demonstrated that compounds 2B and 3B were effective in reducing metastasis (see paragraph 0076 and figure 12). The prior art, Cheng et al. (Cancer Res., 2016, Vol. 76, No. 13, pgs. 3904-3915), teaches that mitochondria targeted analogues exhibit anti-proliferative and radio-sensitizing effects in pancreatic cancer cells (see abstract). Importantly, Cheng et al. demonstrated that metformin analogues containing at TPP moiety and the core structure of metformin were more efficacious in inhibiting mitochondrial complex and in inhibiting cell proliferation (see abstract and see pg. 3905, fig 1A and pgs. 3907-3908, figs. 2-3). Nowhere in the specification or prior art, did applicant demonstrate prevention of any tumor recurrence or metastasis. Additionally, the specification demonstrated that the solely described compound 2B and 3B were effective in reducing tumor cell metastasis (see fig. 12). Nowhere in the specification was it demonstrated that all compounds of the generic formula in claims 2-3 were effective in preventing recurrence or metastasis. Thus, the examiner maintains that prevention of tumor recurrence and metastasis is unlikely and unpredictable.
2. The breadth of the claims
The claims are thus very broad insofar as they recite that the “prevention of tumor recurrence and metastasis with every compound encompass by generic formula delineated in claims 2-3”. While “reduction of tumor recurrence and metastasis” might theoretically be possible by administering the two species of bedaquiline (derivatives compound 2B and compound 3B), as a practical matter it is nearly impossible to achieve the prevention of tumor recurrence and metastasis with every single compound of the generic formula delineated in claims 2 and 3.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides no direction or guidance for the use of the compounds of the generic formula of claims 2 and 3 in preventing tumor recurrence and metastasis. While specific guidance is provided concerning the use of bedaquiline and two bedaquiline derivatives compounds 2b & 3B in reducing migration and metastasis as demonstrated in figures 5, 10, and 12, no actual prevention was shown utilizing said compounds of the generic formula as recited in claims 2 and 3.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence demonstrating the use of the compounds of the generic formula in claims 2 and 3 in preventing tumor recurrence and metastasis, no one skilled in the art would accept the assertion that all compounds encompassed by the aforementioned generic formula of claims 2 and 3 could be predictably used for preventing tumor recurrence and metastasis as inferred by the claims and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Closest Prior art
The closest prior art is Fiorillo et al. (Aging, 2016, Vol. 8, No.8, pgs. 1593-1607, filed on an IDS 1449) who teach bedaquiline as useful in reducing propagation and expansion of breast cancer cells and induced oxidative stress (see abstract). However, Fiorillo et al. do not teach a bedaquiline derivative. Consequently, Fiorillo et al. do not render obvious the instant invention.
Objections
Claims 4-5 and 7-8 are objected to because of the following informalities: Claims are dependent upon rejected claims. Applicant is required to incorporate all of the limitations of said claims into the independent claims. Appropriate correction is required.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Director Bonnie Eyler whose telephone number is 571-272-1200. The Supervisory Primary Examiner can normally be reached on 12:00-8:00 PM EST M-F at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
1 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”.
Prosecution Insights