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 Application
1. Claims 14-23 and 25-26 are pending and subject to examination on the merits. Claim 24 has been withdrawn. Claims 14-23 and 25-26 are currently under examination.
Election/Restrictions
2. Applicant’s election without traverse of species 1: fungi; species 2: leflunomide; species 3: clopidogrel (IUPAC: (s)-methyl-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl)acetate; and species 4: CYP2C19 in the reply filed on 22 May 2026 is acknowledged. Accordingly, claim 24, drawn to non-elected subject matter has been withdrawn.
Priority
3. Acknowledgement is made of applicant’s claim for foreign priority based on an application filed in Germany (DE10 2021 204 094.2) on 25 April 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted on 24 October 2023 has been considered by the examiner. See initialed and signed PTO/SB/08’s.
Drawings
5. The drawings are objected to because in Figure 1 the reactions (structures) are blurry/difficult to read. In Figure 2, “§” should be “3” and there are multiple words that need translation from German to English. 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
6. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on p. 5-10. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
7. Claim 14 is objected to because of the following informalities: in part ii), the claim recites “the prodrug is selected from the group” and should be amended to “the prodrug is selected from the group consisting of” to conform with conventional Markush grouping language and maintain consistency with part i). Appropriate correction is required.
8. Claim 20 are objected to because of the following informalities: periods in claims are not permitted except at the end of the claim and when used for abbreviations (See MPEP 608.01(m)). Thus, it is suggested to replace, for example, “a.” with “(a)” or “a)”, etc. and “i.” with “(i)” or “i)”, etc. It is noted, the preferred format for sequence identifiers is “SEQ ID NO:” – see MPEP 2422.01 and 37 C.F.R. 1821(c) and (d).
Appropriate corrections are required.
FOR SEQ ID NO: - – See MPEP 2422.01 and 37 C.F.R. 1.821(c) and (d)
Claim Rejections - 35 USC § 112(b)
9. 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.
10 Claims 14-23 and 25-26 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.
11. Claim 14 recites the limitation “impaired” in line 2. This is unclear because there is no degree of impairment recited or a wildtype P450 to compare impairment to it. Claims 15-23 and 25-26 are included in the instant rejection, since they do not mitigate the issue.
12. Claim 14 recites the limitation “P450 enzyme set,” in lines 1-2. It is unclear what an enzyme set is, since the specification does not provide a definition of this term. Additionally, it is unclear how many P450 enzymes constitute a set. Claims 15-23 and 25-26 are included in the instant rejection, since they do not mitigate the issue.
13. Claim 19 recites the limitation "the oxidizing agent" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 14 does not recite an oxidizing agent; an oxidizing agent is not mentioned until claim 18.
14. Regarding claim 21, the phrase "in particular" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). All three instances of “in particular” should be deleted from the claim.
15. Regarding claim 23, the phrase "in particular" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The claim should be amended to delete “in particular” from the claim.
Claim Rejections - 35 USC § 103
16. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
17. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
18. Claims 14-23 and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Poraj-Kobielska et al. (Poraj-Kobielska et al., 2011, Biochemical Pharmacology—cited on the Information Disclosure Statement dated 24 October 2023), Dean and Kane (Dean and Kane, 2012, Medical Genetics Summaries—cited herein), and Grabar et al (Grabar et al., 2009, Drug Metabolism and Disposition—cited herein). Regarding claims 14 and 26, drawn to a pharmaceutical composition comprising a liver-specific prodrug, leflunomide and/or clopidogrel, requiring bioactivation by a cytochrome P450 enzyme, with at least one fungal peroxygenase, Poraj-Kobielska et al. teaches the utilization of aromatic peroxygenases from an agaric fungi in the synthesis of hydroxylated and O- or N-dealkylated human drug metabolites via selective monooxygenation (abstract) to aid in the development of safe and effective pharmaceuticals (Introduction). Regarding claims 18-19, drawn to regioselective enzymatic oxyfunctionalization of the prodrug with an oxidizing agent, such as hydrogen peroxide, Poraj-Kobielska et al. teaches the initiation of acetanilide hydroxylation by adding 2.0mM hydrogen peroxide (p. 790, last line-791, first line). Regarding claims 20-21, drawn to the utilization of a non-specific peroxygenease from the enzyme class EC 1.11.2.1 from Agrocybe aegerita, Poraj-Kobielska et al. teaches the utilization of the peroxygenase from Agrocybe aegerita from EC 1.11.2.1 (abstract). Regrading claim 22, drawn to the pharmaceutical composition is in a buffered solution at pH 3-10, Poraj-Kobielska et al. teaches the utilization of the peroxygenase to carry out acetanilide hydroxylation in a potassium phosphate buffer at pH 7.0 (p. 790, 2nd column, last paragraph). Regarding claim 23, drawn to the pharmaceutical composition at a temperature of 4-40oC, Poraj-Kobielska et al. teaches the enzymatic reaction being carried out at 23oC (p. 790, 2nd column, last paragraph).
Poraj-Kobielska et al. does not teach the utilization of the prodrugs, leflunomide and/or clopidogrel (claims 14-15) or the specific enzyme, CYP2C19 (claim 25). Poraj-Kobielska et al. does teach that in vivo, the C-H bonds of pharmaceuticals are predominately oxygenated by liver cytochrome P450-monoxygenases to yield more polar human drug metabolites that are then excreted directly or as conjugates (Introduction, paragraph 1). Regarding the utilization of the prodrug, leflunomide and the P450 enzyme, CYP2C19, Gramar et al. teaches the utilization of leflunomide as a treatment for rheumatoid arthritis and that cytochromes P450, mainly CYP1A2 and CYP2C19 are responsible for the transformation of the prodrug, leflunomide to its metabolite (Abstract). Regarding the utilization of the prodrug, clopidogrel and the P450, CYP2C19, Dean and Kane teach clopidogrel is an antiplatelet medication and that its effectiveness is dependent on its conversion to an active metabolite by CYP2C19 (Introduction).
Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains to combine the teachings of Poraj-Kobielska et al., Gramar et al., and Dean and Kane to utilize a fungal peroxygenase to convert prodrugs, leflunomide and clopidogrel, to active metabolites for the treatment of rheumatoid arthritis and/or cardiovascular disease in individuals with diminished CYP2C19 function, since CYP2C19 is necessary for the conversion in vivo, as taught above. One would be motivated to combine these teachings to arrive at the instant claims, since the fungal peroxygenase from A. aegerita is a stable, secreted enzyme capable of oxidizing a wide range of substrates for biotechnological applications (Column 2, Paragraph 2). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Poraj-Kobielska et al., Gramar et al., and Dean and Kane to utilize a fungal peroxygenase to convert prodrugs, leflunomide and clopidogrel, to active metabolites for the treatment of rheumatoid arthritis and/or cardiovascular disease in individuals with diminished CYP2C19 function, since Poraj-Kobielska et al. demonstrates the utilization of the fungal peroxygenase from A. aegerita as a means to prepare in vitro human drug metabolites.
Conclusion
19. All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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