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 Claims
Claims 1-7 are pending.
Priority
Instant application 18/729,118, filed 07/15/2024 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings are objected to because the drawing sheet labels FIG. 2 as “PRIOR ART”, yet the specification describes FIG. 2 (page 7, lines 20-22) as an embodiment of the invention (“example of activation of the proposed pro-drugs with release of the single active components”). The labeling of FIG. 2 as “PRIOR ART” represents an inconsistency and appears to be a typographical error. If taken at face value, it would read as an applicant admission that the core hybrid-prodrug concept presently claimed is old.
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.
Specification
The disclosure is objected to because of the following informalities: the working examples contain numerous examples of untranslated Italian text in the characterization data. For example, see “Resa 61.0%” on page 11; compound names such as “2-Osso-2H-cromen…” on page 10, “idrossietossi” on page 11, etc. The disclosure should conform to proper idiomatic English. See MPEP 608.01.
Appropriate correction is required.
Claim Interpretation
Claim 1 contains the preamble recitation “A pharmaceutical composition…capable of inhibiting the ATP-dependent proton pump (V-ATPase) and carbonic a-anhydrases (CA IV, IX, and XII)”. This recitation is being interpreted as a functional limitation limiting the claim to compositions which perform the recited function.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 appears to contain multiple typographical errors. First, “pharmaceutical compositions” should read “pharmaceutical composition”. Second, the parenthetical (A, G1-G8) appears to be a superfluous reference to Formula A depicted later in the claim. Applicant is encouraged to remove the parenthetical to avoid confusion. Third, “carbonic a-anhydrases” should read “carbonic anhydrases”.
Appropriate correction is required.
“Use” Claim Rejections – See MPEP 2173.05(q)
Rejection under 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.
Claims 3-7 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.
Claims 3-7 are drawn to a “use” of the compositions according to claim 1 for achieving various outcomes in a patient. The claims are indefinite because they merely recite “using” the composition without providing any active, positive steps delimiting how this use is actually practiced.
Rejection under 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 3-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to nonstatutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because the claims are directed to a “use” of a composition, and do not purport to claim a process, machine, manufacture, or composition of matter. A “use” claim which fails to recite any active, positive steps delimiting how this use is actually practiced is not a process. See MPEP 2106.03 in this regard: “As explained by the Supreme Court, a ‘process’ is ‘a mode of treatment of certain materials to produce a given result. It is an act, or a series of acts, performed upon the subject-matter to be transformed and reduced to a different state or thing.’” See also MPEP 2173.05(q) regarding the eligibility of “use” claims.
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 1-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) 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 inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus …”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed genus is sufficient. See MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
In the instant case, claim 1 (with the substituent definitions of claim 2) is directed to a genus of pharmaceutical compositions comprising a proton-pump inhibitor (PPI) moiety covalently linked to a carbonic anhydrase inhibitor (CAI) moiety, defined as Formula A:
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wherein G1-G8 represent eight structurally distinct CAI scaffolds:
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The genus therefore spans multiple structurally distinct CAI chemotypes, multiple PPI structures, multiple linker chemistries, and an enormous substituent permutation space due to 14+ variable positions. The genus is extraordinarily broad and highly variable. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See MPEP 2163.05(I)(B).
The specification provides four representative species as working examples (A1-A4, page 13):
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Each is the same PPI (lansoprazole), joined by the same linker type (a carbamate), to the same CAI chemotype (a coumarin). The only differences are the alkoxy linker length (n = 1 or 2) and the ring position (6- or 7-). The specification also provides enzyme inhibition data (Table 1) and cell mortality data (FIGS 7-11).
The disclosed examples are not representative of a genus defined by eight CAI chemotypes, multiple PPIs, and multiple linkers. No other conjugates comprising a different PPI, a different linker, or a different “G” group are disclosed. A “representative number of species” means species that reflect the variation across the genus. Structurally similar species that occupy one narrow region do not suffice.
Neither the specification nor the prior art supplies a structure-function correlation that would allow a person having ordinary skill in the art to recognize, from the four disclosed coumarin species, that the inventors possessed the remaining genus. The claimed CAI scaffolds (G1-G8) inhibit carbonic anhydrase by mechanistically distinct modes with divergent structure-activity relationships. Possession of an active coumarin conjugate does not convey possession of active sulfonamide, benzoxaborole, dithiocarbamate, or thiuram-disulfide conjugates, nor that any such conjugate will retain CA inhibition once tethered to the bulky PPI, will function as a hydrolysable pro-drug in the acidic tumor microenvironment, and will release both active species.
The prior art establishes that co-administration of a PPI with a CAI was a known strategy. See, for example, FEDERICI (Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 31, no. sup1, Nov. 2016, pp. 119–25). Federici discloses that the PPI lansoprazole and carbonic anhydrase IX inhibitors (F9-399A and S4) synergize against human melanoma cells (Federici, title; abstract; discussion; conclusions). See also IESSI (Metabolites, vol. 8, no. 1, Dec. 2017, p. 2). Iessi provides an overview of the strategy of combining proton pump inhibitors with carbonic anhydrase inhibitors to treat cancer (Iessi, title; abstract; conclusions).
While the strategy of combining discrete PPI and CAI compounds to treat cancer was generally known, the prior art did not teach or suggest preparing a conjugate/hybrid compound containing both PPI and CAI moieties, nor did the prior art establish a structure-function correlation to achieve functional compounds comprising both PPI and CAI moieties. Close prior art relating to hybrid CAI compounds is BUA et al. (Journal of Medicinal Chemistry, vol. 60, no. 3, Feb. 2017, pp. 1159–70). Bua discloses the design and synthesis of novel nonsteroidal anti-inflammatory (NSAID) and CAI hybrids (NSAID-CAIs) for the treatment of rheumatoid arthritis (Bua, title, abstract, Figure 2). Bua demonstrates that the positions for substitution on a coumarin-containing hybrid molecule (6- or 7-) were generally known. However, because Bua is drawn to NSAID-CAI hybrids, it provides no direction or guidance for preparing PPI-CAI hybrids. Additionally, because Bua only provides coumarin-based hybrids, it provides no direction or guidance for preparing PPI-CAI hybrids containing a sulfonamide, benzoxaborole, dithiocarbamate, or thiuram-disulfide CAI moiety.
To the extent the genus in claim 1 is defined partly by the functional recitation that the composition is “capable of inhibiting the ATP-dependent proton pump (V-ATPase) and carbonic a-anhydrases (CA IV, IX, and XII), “function alone typically will not suffice to sufficiently describe the composition”. See MPEP 2163(II)(A)(3)(a).
For the reasons above, the specification does not reasonably convey that the inventors possessed the full genus of conjugates recited in claims 1 and 2 as of the priority date. The four disclosed coumarin-carbamate-lansoprazole species are neither a representative number of species across the genus nor accompanied by a structure-function correlation (disclosed or art recognized) sufficient to demonstrate possession of the broad PPI inhibitor space other than lansoprazole, of linkers other than carbamate, or of the G2-G8 branches of Formula A.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, in view of the foregoing analysis, the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claims 1 and 2 are therefore rejected under section 112(a). Dependent claims 3-7 do not resolve these issues, since these claims do not further limit the structure of the genus of claim 1. Accordingly, these claims are also rejected.
Claim 4 additionally recites a broad set of indications (hypoxic/metastatic tumors, gastrointestinal disorders, inflammation, arthritis, pathogenic infections, gastrointestinal toxicity associated with NSAIDs) for which the specification provides no data beyond the oncology cell-based results. The absence of support across that range of uses provides a further basis for the rejection as to claim 4.
The rejection may be overcome by amending the claims to recite subject matter commensurate with the written description. For example, limiting the claims to the disclosed CAI chemotype, PPI, and linker (e.g. lansoprazole-carbamate-hydroxyalkyloxy-coumarin conjugates, or a modest subgenus reasonably supported by the working examples).
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.
Claims 1-7 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.
Claim 1 recites a compound having the general formula:
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.
A significant number of variables in the above compound formula are undefined in claim 1, including R1-R8, X1, X2, Y1, Y2, R9-R14, Z1, and Z2. A claim term with no ascertainable meaning and no antecedent basis is indefinite. See MPEP 2173.05(e). Claims 3-7 depend from claim 1 and fail to resolve the issue above.
Therefore, claims 1 and 3-7 are indefinite.
Claim 2 defines R1-R14 (and X1, X2, Y1, Y2, Z1, and Z2), each “independently” as roughly twenty functional group classes “…or more of them,” across eight structurally diverse carbonic anhydrase inhibitor scaffolds. Claim 2 presents multiple issues:
First, claim 2 recites the limitation “Gn” in line 2. There is insufficient antecedent basis for this limitation in the claim. It is unclear why “Gn” is defined here when there is no “Gn” present in Formula A depicted in claim 1.
Second, claim 2 recites that “X1, X2, Z1, Z2 = O, S”. It is unclear if this recitation is intended to mean that X1, X2, Z1, and Z2 are each independently selected from the group consisting of O and S, or if some other interpretation (X1 = O, X2 = S; Z1 = O, Z2 = S) is intended. Due to the ambiguity of the limitation and conflicting interpretations, the limitation is indefinite. Similarly, the limitation “Y1, Y2 = alkyl, alkenyl, alkynyl…” is ambiguous and indefinite. These limitations should be written as proper Markush groups if that is the intended interpretation.
Third, the phrase “or more of them” at the end of claim 2 leaves the Markush group open,
which is indefinite. See MPEP 2173.05(h), which states: “[a] Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members…[i]f a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim.”
Fourth, where a chemical claim defined by Markush groups encompasses a massive number of distinct alternative members such that one skilled in the art cannot determine its metes and bounds (i.e., cannot envision all the compounds), the claim is indefinite under section 112(b). See MPEP 2173.05 (h), which states: “[f]or example, if a claim defines a chemical compound using one or more Markush groups, and that claim encompasses a massive number of distinct alternative members, the claim may be indefinite under 35 U.S.C. 112(b) if one skilled in the art cannot determine its metes and bounds due to an inability to envision all of the compounds defined by the Markush group(s). In such a circumstance, a rejection of the claim for indefiniteness under 35 U.S.C. 112(b) is appropriate.”
Therefore, in view of the foregoing issues, claim 2 is indefinite.
Claims 4-6 recite the limitation “The use…according to claim 1” in line 1. There is insufficient antecedent basis for this limitation in the claim. There is no antecedent “use” in claim 1. Similarly, the limitation “the target tissue” in claims 5 and 6 lacks antecedent basis. Therefore, claims 4-6 are indefinite.
Claim 7 recites the phrase “characterized by a predetermined dosage”, yet fails to actually specify an actual dosage. MPEP 2173.05(c) lists, as a held-indefinite example, “a predetermined quantity, for example, the maximum capacity.” Therefore claim 7 is indefinite.
Conclusion
Claims 1-7 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 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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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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