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 .
Acknowledgement of Receipt
Applicant’s Response, filed 8/8/2025, in reply to the Office Action mailed 7/28/2025, is acknowledged and has been entered. Claims 1 and 13 have been amended. Claims 1-19 are pending and are examined herein on the merits for patentability.
Response to Arguments
Any rejection or objection not reiterated herein has been withdrawn as being overcome by claim amendment. The provisional double patenting rejection has been withdrawn in view of the terminal disclaimer filed 8/8/2025.
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) 1-19 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), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that although Das discloses that SBE6.5-B-CD can be used to improve the solubility and stability of melphalan and therefore provides a motivation for one skilled in the art to attempt to use SBE6.5-B-CD to solubilize Compound (1c)-HC1, Das does not provide an expectation that SBE6.5-B-CD can improve the solubility and stability of simply any compound. Applicant asserts that Table 3 of Das indicates that the effect of SBE6.5-B-CD on a particular drug can be very different and not necessarily result in increased solubility and stability of the drug. Applicant argues that the three-dimensional structures melphalan and Compund (1c) are very different, such that the orientation of the bis(2- chloroethyl)amino (nitrogen mustard) group is different for the two compounds. Applicant asserts that because melphalan and Compound (1c) have a substantially different three- dimensional structure there cannot be any expectation of similar properties.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that obviousness does not require absolute predictability, see MPEP 2143. Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).
See also MPEP 2144.08. Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g.,In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). In the instant case, it is noted that the Das reference as cited by Applicant shows that a variety of structurally diverse compounds are stabilized / solubilized by the commercially available SBE6.5-B-CD solubilizing agent, i.e. including compounds which are more dissimilar in structure than melphalan and compound 1. Das states that SBE-β-CD has been reported as one of the best solubility enhancers. It has been extensively used for formulation of drags with poor water solubility and also recites that SBE-β-CDs have been reported to enhance stability of many dregs compared to other CDs (see pages 591-4). As such it is considered that a person of ordinary skill in the art would have had at least a reasonable expectation that the captisol would solubilize / stabilize the claimed compound in a manner similar to structurally and functionally similar melphalan.
Applicant further argues that experimental results demonstrate the improved solubility and stability of the (S)-3-amino-4-(5-(bis(2- chloroethyl)amino)-2-methylphenyl)butanoic acid hydrochloride / SBE6.5-B-CD complex compared to other solubilizing/stabilizing formulations. In Example 3, the Applicant demonstrates that Compound (1c)-free base is not stable in pH 7.4 phosphate buffered saline at 37 °C. However, as shown in Example, 4, when complexed with SBE6.5-B-CD, Compound (1c)-free base at a concentration from 0.5 mg/mL to 2.0 mg/mL exhibited improved stability at 25 °C. Applicant argues that as demonstrated by the experimental results presented in Example 9 not all formulations that are effective in improving the solubility and stability of a structurally similar compound are equally effective in improving the stability of Compound (1c)-HCl, and that the superior stability of the Compound (1c)-HCl / SBE6.5-B-CD complex compared to other stability-promoting formulations represents an unexpected result in view of Jandeleit and Pipkin.
Applicant’s arguments have been fully considered but are not found to be persuasive. See MPEP 716.02. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (differences in sedative and anticholinergic effects between prior art and claimed antidepressants were not unexpected). In In re Waymouth, 499 F.2d 1273, 1276, 182 USPQ 290, 293 (CCPA 1974), the court held that unexpected results for a claimed range as compared with the range disclosed in the prior art had been shown by a demonstration of "a marked improvement, over the results achieved under other ratios, as to be classified as a difference in kind, rather than one of degree." Compare In re Wagner, 371 F.2d 877, 884, 152 USPQ 552, 560 (CCPA 1967) (differences in properties cannot be disregarded on the ground they are differences in degree rather than in kind); Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) ("we generally consider a discussion of results in terms of ‘differences in degree’ as compared to ‘differences in kind’... to have very little meaning in a relevant legal sense"). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023) ("A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent.").
In the instant case, it is respectfully submitted that at least some differences between commercially available solubilizing agents may be expected to result in some differences in properties. For example, see Singh et al. (Pharm Dev Technol, 2018, 23(10), p. 1024-1029), provided in rebuttal to Applicant’s allegation of unexpected results. For example, Singh shows that formulation of structurally similar melphalan with Captisol technology significantly improved stability compared to melphalan hydrochloride reconstituted with propylene-glycol based diluents. Applicant’s arguments have been fully considered but the rejection is maintained.
Conclusion
No claims are allowed at this time.
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.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618