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 .1
Status of the Claims
Claims 1, 4-6, 8-9 and 11-12 are pending in this application and are under examination, certain species of triazole antifungals were rejoined. 2
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SCY-078 Isavuconazole
Response to Arguments
Applicant's arguments filed April 22, 2026 have been fully considered but they are not persuasive with regard to the rejection of claims 1 and 4-12 as being obvious over Merck WO 203 in view of Girmenia. See modified rejections below and rebuttal of the Attorney response.
Applicant's arguments filed April 22, 2026 have been fully considered but they are not persuasive with regard to the rejection of claims 1 and 4-12 as being rejected for obviousness-type double patenting over U.S. Patent No. 8,188,085 (the "reference patent"), in view Merck WO 203 and Girmenia. See modified rejections below and rebuttal of the Attorney response.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 4-6, 8-9 and 11-12 remain rejected under 35 U.S.C. 103 as being unpatentable over WO 2010/019203 A1 (Merck WO ‘203), in view of Girmenia (2009) New generation azole antifungals in clinical investigation, Expert Opin Investig Drugs, 18:9, 1279-1295. Merck WO ‘203 (Ref. BC) is cited by Applicant on the 8/10/2021 IDS. Girmenia is cited on the PTO-892 form dated 11/15/2024.
Claims 1 and 4 are directed to a pharmaceutical combination of a compound of the formula (II or IIa) such as elected species SCY-078 and a triazole antifungal agent isavuconazole, wherein the weight ratio of the compound of formula (Ila) to isavuconazole ranges from 1:16 to 3:16.
Merck WO ‘203 discloses elected species SCY-078, Example 173 found on page 94, reproduced below.
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Merck WO ‘203 discloses SCY-078 and other enfumafungin derivatives (page 11, line 16) taught in combination with triazole anti-fungal compounds; Merck WO 203 teaches SCY-078 in combination with triazole antifungals, voriconazole, itraconazole, ketoconazole, miconazole, and posaconazole, (see page 9, lines 4-9).
While Merck WO 203 teaches a pharmaceutical composition of SCY-078 with various triazole antifungals, it does not teach the elected species of isavuconazole. However, based on the teachings in the art, a person having ordinary skill in the art (PHOSITA) would substitute it for other known triazole-type anti-fungal drugs.
Isavuconazole has demonstrated particular advantages in comparison to other triazole anti-fungal drugs, where Girmenia teaches food does not affect absorption of isavuconazole (i.e. can be taken with or without food, unlike other azole anti-fungal drugs such as fluconazole, itraconazole, voriconazole, posaconazole, etc.). See Table 1 page 1281. Further Table 1 of Girmenia teaches isavuconazole has the highest maximum plasma concentration per 100 mg when compared to the other triazole antifungals, etc., with a longer half-life (56 h to 104 h) than those of fluconazole, itraconazole, voriconazole, and posaconazole. Also per Table 2, Girmenia teaches equivalent if not superior in vitro activity against Aspergillus spp. mold infection. See page 1285.
Regarding the limitations of ratios of formula (II) to isavuconazole ranges from 1: 16 to 3: 16, Merck WO 203, teaches dose ranges of its compounds 0.001 to 1000 mg/kg, 0.01 to 500 mg/kg, 0.1 to 100 mg/kg; or alternatively, 1.0 to 500 mg, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100,150,200,250,300,400, and 500 milligrams (page 14, lines 19-28), where Girmenia teaches doses of 100 mg of isavuconazole. See Table 1 page 1281. As noted by the teachings of Merck WO 203, it would be routine for a PHOSITA to optimize such ratio of SCY-078 to isavuconazole based on the known doses of both, to achieve the proper claimed ratio for every individual patient. 3
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of Merck WO 203 to combine SCY-078 with other anti-fungal compounds (triazole antifungals) modified with the teachings of Girmenia in order to substitute isavuconazole to arrive at the claimed combination.
The PHOSITA would have had a reasonable expectation of success because the rationale to do so would be the combination of compounds known for the same purpose to be predictably combined as being obvious. A PHOSITA would have had a rationale to substitute a functional equivalent of one triazole antifungal with another such as isavuconazole, which demonstrates superior properties as taught by Girmenia vs. other triazole antifungals.
As required by claims 5 and 8 recites where formula II or IIa (SCY-078) is in an amount of 50 mg to 1000mg, Merck WO 203, teaches dose ranges of its compounds 0.001 to 1000 mg/kg, 0.01 to 500 mg/kg, 0.1 to 100 mg/kg; or alternatively, 1.0 to 500 mg, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100,150,200,250,300,400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. See page 14, lines 19-28.
As required by claims 6 and 9 recites where the amount of triazole antifungal, isavuconazole, in an amount of 50 to 1000 mg, Girmenia teaches doses of 100 mg of isavuconazole. See Table 1 page 1281. 1
Regarding claims 11-12, Merck WO 203 teaches all compounds of the present invention may be administered in the form of “pharmaceutically acceptable salts.” See page 11, line 23. Merck WO 203 teaches representative pharmaceutically acceptable salts include citrate salts. See page 12, lines 8-9.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states neither Merck nor Girmenia, alone or in combination, teaches or suggests the pharmaceutical combination. The Attorney response states Merck does not disclose or suggest isavuconazole, or combinations thereof with a compound of Formula II or IIa.
The Attorney response states the claimed weight ratio is a parameter that a PHOSITA would not have routinely optimized based on the individual dose amounts disclosed in Merck '203 and Girmenia. The Attorney response states that the relative proportion (i.e., weight ratio) of the two drugs is a variable that affects any relevant property, where at most, the art teaches independent dosing of each drug.
The Attorney response states the Examiner improperly equates independent dose selection with selection of a coordinated weight ratio, which is a distinct limitation requiring that the two drugs be proportioned relative to one another, where there is no meaningful starting point for any purported optimization, based on hindsight reconstruction provided by Applicant.
The Attorney response argues that the claims require a defined weight ratio, not the possibility that two independently titrated doses might coincidentally fall within that ratio, with teaching of an adjustment.
In response, Merck WO ‘203 explicitly teaches the combination of claimed SCY-078 in combination with triazole antifungals, where it has been established it is prima facie obvious, to substitute isavuconazole per Girmenia, with those of Merck ‘203.
With regard to the claimed ratio range 1:16 (6.25:100) to 3:16 (18.75:100), Merck WO ‘203 not only establishes the claimed combination in view of Girmenia, it teaches that “effective amounts” and “therapeutically effective amounts” of its compounds are those sought to elicit a medical response in a subject, by a researcher, doctor, vet or clinician (a PHOSITA), necessary for the alleviation of symptoms the disease/condition to be treated. See page 13, lines 12-18.
Merck ‘203 teaches its compounds can be administered individually or in a combination of therapeutic agents (see page 13, lines 28-29), in this case isavuconazole, in view of Girmenia. As detailed above, the dose of the active ingredient of Merck’ 203 can be from 1-500 mg, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100,150,200,250,300,400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. It is already prima facie obvious to combine SCY-078 per Merck with isavuconazole per Girmenia, which teaches a dose of 100 mg.
While these are separate doses of each compound from both references, as Merck ‘203 in view of Girmenia teaches the combination, the adjustment of doses by a PHOSITA and the combination therapy by a PHOSITA, the claimed range of ratios 6.25:100 to 18.75:100 is encompassed by known doses of the two combined compounds, as known in the art, 10 mg SCY-078 : 100 mg isavuconazole to 20 mg SCY-078 : 100 mg isavuconazole. While the Attorney response argues the claims require a specific weight ratio, as the cited art teach amounts of doses (in a dose weight to be administered to a subject in need) and teach the combination as claimed, the PHOSITA would routinely arrive at the claimed weight ratio.
Non-Statutory Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4-6, 8-9 and 11-12 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-51 of US Patent 8,188,085 B2 (085 patent, the reference patent) in view of WO 2010/019203 A1 (Merck WO ‘203) and Girmenia (2009) New generation azole antifungals in clinical investigation, Expert Opin Investig Drugs, 18:9, 1279-1295.
With regard to claims 1 and 4 and the combination of formula II or IIa and isavuconazole, US Patent 8,188,085 B2 generally claims compounds of formula I,
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which generically covers applicant’s claimed compounds of formula II and/or IIa, see claim 1 and so forth , with species with the same scope as those claimed.
Claim 1 of the 085 patent (reference patent) teaches a compound of formula (I) that teaches SCY-078 when:
R1 is 1,2,4-triazol-1-yl substituted with 4-pyridine;
R2 is 2-amino-2,3,3-trimethylbutyl ; and
R3 is C(O)-OH.
X is absent.
The 085 patent reference patent specifically claims the compound of formulas II/IIa, see reference claims 44 and 49 for example, as well as combinations with other antifungal compounds to treat fungal infections such as Aspergillus, see claims 45-51.
Reference claim 44 discloses compound SCY-0784
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at column 1, lines 35-40.
Reference patent claim 49 is directed solely to the single compound or a pharmaceutically acceptable salt, also known as SCY-078 (see Footnote 3).
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See Example 173 for definition of the structure5, columns 269-270.
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As per claim 46 of the reference patent, it claims a composition according to claim 45 (i.e. the compounds above), further comprising a second therapeutic agent.
Regarding the combination of claims 1 and 4, Merck WO ‘203 discloses enfumafungin derivatives of claim 1. See page 11, line 16. The elected species, SCY-078 and other enfumafungin derivatives are taught in combination with voriconazole, itraconazole, ketoconazole, miconazole, ravuconazole, detoconazole, clotrimazole, and posaconazole, (see page 9, lines 4-9).
While the reference patent and Merck WO 203 teaches the claimed pharmaceutical composition of SCY-078 and various triazole antifungals, it does not teach the elected species of isavuconazole as per claims 1 and 4. See above. However, the art provides teachings to look towards the triazole antifungal isavuconazole as claimed.
Isavuconazole has demonstrated particular advantages in comparison to other triazole anti-fungal drugs, where Girmenia teaches food does not affect absorption of isavuconazole (i.e. can be taken with or without food, unlike other triazole anti-fungal drugs such as fluconazole, itraconazole, voriconazole, posaconazole, etc.). See Table 1 page 1281. Further Table 1 of Girmenia teaches isavuconazole has the highest maximum plasma concentration per 100 mg when compared to the other triazole antifungals, etc., with a longer half-life (56 h to 104 h) than those of fluconazole, itraconazole, voriconazole, and posaconazole. Also per Table 2, Girmenia teaches equivalent if not superior in vitro activity against Aspergillus spp. mold infection. See page 1285. One of ordinary skill in the art would have a rationale to substitute a functional equivalent of one triazole antifungal with another such as isavuconazole, which demonstrates super properties as taught by Girmenia.
Regarding the limitations of ratios of formula (II) to isavuconazole ranges from 1: 16 to 3: 16, Merck WO 203, teaches dose ranges of its compounds 0.001 to 1000 mg/kg, 0.01 to 500 mg/kg, 0.1 to 100 mg/kg; or alternatively, 1.0 to 500 mg, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100,150,200,250,300,400, and 500 milligrams (page 14, lines 19-28), where Girmenia teaches doses of 100 mg of isavuconazole. See Table 1 page 1281. As noted by the teachings of Merck WO 203, it would be routine for a PHOSITA to optimize such ratio of SCY-078 to isavuconazole based on the known doses of both, to achieve the proper claimed ratio for every individual patient. 6
A PHOSITA would have found it prima facie obvious to combine SCY-078, a known antifungal with other known antifungals, such as those elected species of triazole antifungals. A PHOSITA would have a rationale to combine SCY-078 with said azole antifungals with a reasonable expectation of success as such combinations are known in the art and substitution of isavuconazole is suggested due its superior properties.
As required by claims 5 and 8 recites where formula II or IIa (SCY-078) is in an amount of 50 mg to 1000mg, Merck WO 203, teaches dose ranges of its compounds 0.001 to 1000 mg/kg, 0.01 to 500 mg/kg, 0.1 to 100 mg/kg; or alternatively, 1.0 to 500 mg, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100,150,200,250,300,400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. See page 14, lines 19-28.
As required by claims 6 and 9 recites where the amount of triazole antifungal, isavuconazole, in an amount of 50 to 1000 mg, Girmenia teaches doses of 100 mg of isavuconazole. See Table 1 page 1281.
Regarding claims 11-12, Merck WO 203 teaches all compounds of the present invention may be administered in the form of “pharmaceutically acceptable salts.” See page 11, line 23. Merck WO 203 teaches representative pharmaceutically acceptable salts include citrate salts. See page 12, lines 8-9.
RESPONSE TO THE ATTORNEY ARGUMENTS:
The Attorney response states none of the claims of the reference patent are directed to the claimed pharmaceutical combination or its claimed weight ratio (SCY-078 : isavuconazole from weight ratios 1:16 to 3:16).
In response, a PHOSITA would have found it prima facie obvious to combine SCY-078, a known antifungal with other known antifungals, such as the elected species of triazole antifungal, isavuconazole, as spelled out in the rejection. While the Attorney response argues the claims require a specific dose ratio 1:16 (6.25:100) to 3:16 (18.75:100), the claimed range of ratios 6.25:100 to 18.75:100 is encompassed by known doses of the two combined compounds, as known in the art, 10 mg SCY-078 : 100 mg isavuconazole to 20 mg SCY-078 : 100 mg isavuconazole.
The cited art teach amounts of doses (in a dose weight to be administered to a subject in need) and teach the combination as claimed, the PHOSITA would routinely arrive at the claimed ratio.
Conclusion
No claims are allowed. THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621
1 This application is a divisional of USSN: 15/945,428 filed on 04/04/2018 and issued as US PAT 11110102 on Aug 18 2021.USSN 15/945,428 claims priority to 62/483,647 filed on 04/10/2017.
2 The examined species of the second therapeutic compound has been expanded to include other triazole-type antifungals, voriconazole, isavuconazole, posaconazole, itraconazole) and amphotericin B as claimed by applicant. As detailed before, this case is a divisional of parent case, USSN 15945428. Previously examined claims 1-12 correspond with non-elected Group I from the parent case, a combination of elected species formula II (SCY-078) and the elected species of isavuconazole. Accordingly, pending examined claims 1-12 receive 35 USC 121 protection (safe harbor) from obviousness-type double patenting rejections filed as a result of the July 2 2019 restriction requirement.
3 The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight) general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. See Merck WO 203, page 14, lines 28-32.
4 1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid
5 The specification’s Example 173 is properly relied upon to construe the reference claim so as to provide the structure of the compound that teaches the claimed subject matter, compound SCY-078.
MPEP § 804 Proper Uses of the Disclosure in an ODP-Obviousness Analysis “[T]hose portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent.”
6 The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight) general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. See Merck WO 203, page 14, lines 28-32.
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