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 18, 19 and 22-28, 30 and 32-37 are pending and are examined herein on the merits for patentability.
Double Patenting
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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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/apply/applying-online/eterminal-disclaimer.
Claims 18, 19 and 22-28, 30 and 32-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/217,909 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. The instant claims are directed to a lyophilizate guest-host inclusion complex comprising: (S)-3-amino-4-(5-(bis-chloroethyl)amino)-2-methylphenyl) butanoic acid mono- hydrochloride; and sulfobutyl ether-β-cyclodextrin having an average degree of substitution of 6.5, wherein a mass ratio of the (S)-3-amino-4-(5-(bis-chloroethyl)amino)-2-methylphenyl) butanoic acid mono-hydrochloride to the sulfobutyl ether-β-cyclodextrin is from 1:50 to 1:60. The claims of the ‘909 Application are directed to a guest-host inclusion complex comprising: (S)-3-amino-4-(5-(bis(2-chloroethylamino)-2-methylphenyl)butanoic acid or a pharmaceutically acceptable zwitterion, internal salt, or salt thereof; and a sulfobutyl ether-β-cyclodextrin or a pharmaceutically acceptable zwitterion, internal salt, or salt thereof having an average degree of substitution (ADS) of from 6 to 8 (SBE6-8-β-CD) Wherein the mass ratio of the (S)-3-amino-4-(5-(bis(2-chloroethyl)amino)-2-methylphenyl)butanoic acid or a pharmaceutically acceptable zwitterion, internal salt, or salt thereof to the sulfobutyl ether-β-cyclodextrin or a pharmaceutically acceptable zwitterion, internal salt, or salt thereof is from 1:50 to 1:60. Dependent claim 6 includes wherein the host guest complex is a lyophilizate. Accordingly, the claims are overlapping in scope and are obvious variants of one another. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 18, 19, 22-28, 30 and 32-37 are rejected under 35 U.S.C. 103 as being unpatentable over Jandeleit (US 2016/0346240) in view of Pipkin et al. (US 2010/0311838).
Jandeleit teaches a method of reducing the effects of chemotherapy on normal/healthy cells in a patient being treated for cancer or abnormal cell proliferation, comprising: administering to the patient a therapeutically effective amount of a cell cycle inhibitor; and administering to the patient a therapeutically effective amount of a chemotherapeutic compound comprising a compound of Formula (1):
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(claim 1).
See also claim 9 and Example 5, directed to (3S)-3-Amino-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butanoic acid (5).
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.
The cancer includes brain cancer (claim 15).
In certain embodiments, a compound of Formula (1) or a pharmaceutical composition comprising a compound of Formula (1) may be administered to treat a cancer known to be treated by an alkylating agent, such as, for example, melphalan (paragraph 0550).
In Example 38, mouse melanoma cells were implanted into syngeneic mice. Treatment began when the tumors reached a volume of 40 mm3 at which time the animals were dosed daily for 12 days with either melphalan (control) or compound (5). The size of the tumor and the white blood count were measured. The results are presented in FIG. 2 and FIG. 3. The results show that compound 5 suppressed tumor growth. Tumors began to grow after dosing of compound 5 ended at 12 days. The white blood cell count remained within the normal range during treatment with compound (5).
In certain embodiments, pharmaceutical compositions comprising a compound of Formula (1) may be administered with one or more substances to enhance, modulate and/or control release, bioavailability, therapeutic efficacy, therapeutic potency, stability, and the like of a compound of Formula (1) (paragraph 0570).
Jandeleit does not specifically teach wherein (3S)-3-Amino-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butanoic acid is in the form of a host/guest inclusion complex with sulfobutyl ether-beta-cyclodextrin.
Pipkin teaches pharmaceutical compositions comprising melphalan and a cyclodextrin derivative, and methods of making and using the same.
The present invention is directed to a pharmaceutical composition comprising 25 mg to 125 mg of melphalan as a hydrochloride salt, an optional buffer,
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(melphalan)
and a cyclodextrin derivative of formula I
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wherein n is 4, 5 or 6; wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are independently --H, a straight-chain or branched C1-C8-(alkylene)-SO3- group, or an optionally substituted straight-chain or branched C1-C6 group; wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is a straight-chain or branched C1-C8-(alkylene)-SO3- group; wherein the pharmaceutical composition has a pH of about 4 to about 6; wherein dilution of the pharmaceutical composition with an aqueous solution provides a melphalan solution ready for infusion in which the melphalan degrades by 2% or less at about 25 C within 5 hours, or 4% or less at about 25 C within 10 hours after the dilution; and wherein the cyclodextrin derivative is present in a ratio of 50:1 to 100:1 (w/w) relative to the melphalan (paragraph 0012).
In some embodiments, the cyclodextrin derivative is a compound of formula II:
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wherein R=(H)21-x or (--(CH2)4--SO3-Na+)x, and x=6.0-7.1; and the pharmaceutical composition comprises about 50 mg of melphalan as a hydrochloride salt and the cyclodextrin derivative is present in a concentration of 50:1 to 100:1 (w/w) relative to the melphalan; or the pharmaceutical composition comprises about 50 mg of melphalan as a hydrochloride salt the cyclodextrin derivative is present in a ratio of about 55:1 (w/w) relative to the melphalan (paragraph 0015-17).
Lyophilization is taught, see Figure 3.
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See also Examples 4 and 5, which are directed to a pharmaceutical composition comprising melphalan as a hydrochloride salt was prepared by the process outlined schematically in FIG. 3. SBE6.5-beta-CD, CAPTISOL was added slowly while vortex stirring, and the resulting solution was stirred for about 15 minutes to ensure complete dissolution. The resulting solution had a pH of about 2.5. Melphalan as a hydrochloride salt (516 mg) was added slowly while vortex stirring, and the resulting solution was stirred for about 15 minutes to ensure complete dissolution. A base (2 N NaOH) was then slowly added while vortex stirring until the solution had a pH of about 5.6. The solution was then assayed using a UV/vis spectrophotometer (detection wavelength of 260 nm). The solution comprised melphalan at a concentration of 5.16 mg/mL, and the melphalan was present in a ratio of about 1:55 w/w relative to the cyclodextrin derivative. The solution was then passed through a sterile filter (0.22 .mu.m PVDF) and cooled to 10-15 C. In Example 5, the liquid pharmaceutical composition provided in Example 4 was lyophilized to provide a reconstitutable and/or dilutable dry powder comprising 50 mg of melphalan as a hydrochloride salt. Glass vials were filled with the solution (10 mL) and placed in trays on a pre-cooled shelf at 5 C. The vials were allowed to thermally equilibrate for about 30 minutes, and were then lyophilized to provide a dry powder in each vial. The vials were back-filled with nitrogen at a pressure of about 400 mTorr, and then sealed.
The invention is directed to a method of treating a subject suffering from a neoplastic disorder, the method comprising diluting a composition with an aqueous diluent to provide a dilute pharmaceutical composition comprising 25 mg to 125 mg of melphalan and a cyclodextrin derivative of formula I. The neoplastic disorder includes various cancers, see paragraph 0020-21.
In some embodiments, the cyclodextrin derivative is a sulfobutyl ether-beta-cyclodextrin having an ADS of about 7 (e.g., CAPTISOL, CyDex Pharmaceuticals, Inc., Lenexa, Kans.). CAPTISOL cyclodextrin is a polyanionic beta-cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cyclodextrin cavity by a butyl ether spacer group, or sulfobutylether (SBE). CAPTISOL cyclodextrin has been shown to be safe when administered parenterally, orally, or via inhalation and does not exhibit the nephrotoxicity associated with beta-cyclodextrin. Relative to beta-cyclodextrin, CAPTISOL sulfoalkyl ether cyclodextrin provides comparable or higher complexation characteristics and superior water solubility in excess of 90 g per 100 mL, a 50-fold improvement. Melphalan has a low binding affinity with CAPTISOL (Ka=3x102 M-1) (paragraph 0066).
In some embodiments, a unit dosage form of the present invention is a solid. In some embodiments, a solid unit dosage form of the present invention is a lyophilized solid or an aseptic spray-dried solid. In some embodiments, a dosage form of the present invention is suitable for dilution and/or reconstitution with a predetermined amount of a liquid carrier. For example, a unit dosage form (e.g., a liquid or a solid) of the present invention can be diluted with 5 mL to 500 mL, 10 mL to 100 mL, or 10 mL to 50 mL of a liquid carrier (paragraph 0100).
In some embodiments, after dilution melphalan is present in the diluted pharmaceutical composition in a concentration of 0.1 mg/mL to 50 mg/mL (paragraph 0089). In some embodiments, a diluent consists essentially of water and optional tonicity-adjusting agents (e.g., 0.9% saline solution for injection, and the like) (paragraph 0090).
The melphalan hydrochloride salt displayed a significant solubility enhancement compared to free base melphalan for all cyclodextrin derivative concentrations above 25 mM (paragraph 0156).
In some embodiments, the bioavailability of melphalan from a composition of the present invention is greater than that observed upon administration of an equivalent dose of melphalan from a formulation lacking a cyclodextrin derivative (paragraph 0142).
In some embodiments, the pharmaceutical compositions of the present invention provide a reduced rate of severe myelotoxicity in patients (e.g., patients who experience a white blood cell count <1,000 per mL and/or platelet count <25,000) after parenteral administration compared with patients parenterally administered a similar dose of melphalan without a cyclodextrin derivative (paragraph 0146).
Dilute solutions such as 0.45 mg/mL melphalan are taught (paragraph 0173.)
It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute (3S)-3-Amino-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butanoic acid for melphalan as a structurally similar chemotherapeutic agent in a lyophilized host/guest inclusion complex with sulfobutyl ether-beta-cyclodextrin at a ratio of 1:50 or 1:55, as taught by Pipkin, when the teaching of Pipkin is taken in view of Jandeleit. One would have been motivated to do so, with a reasonable expectation of success, because Jandeleit teaches that a compound of Formula (1) may be administered to treat a cancer known to be treated by an alkylating agent, such as melphalan; and further showed that compound 5 suppressed tumor growth. Jandeleit further teaches treatment of brain cancer. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted compounds have similar structure and function and substation of one for another would have been predictable. Further, Jandeleit teaches that Formula (1) may be administered with one or more substances to enhance, modulate and/or control release, bioavailability, therapeutic efficacy, therapeutic potency, stability, and the like of a compound of Formula (1) (paragraph 0570); and Pipkin teaches that sulfobutyl ether-beta-cyclodextrin increased bioavailability and reduced toxicity of melphalan compared to melphalan without a cyclodextrin derivative.
See MPEP 2144.09, directed to rejection based on close structural similarity is founded on the expectation that compounds similar in structure will have similar properties. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618