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 5/12/2026, in reply to the Office Action mailed 1/23/2026, is acknowledged and has been entered. Claim 37 has been amended. Claims 18, 19, 22-28, 30 and 32-37 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn. The Examiner’s response to Applicant’s arguments is incorporated below.
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), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues in Section 1 of the Response, The Compound-Specific and Inherently Unpredictable Nature of Cyclodextrin Stabilization, that the reliance of the Office on Pipkin and related prior art concerning melphalan cannot establish a prima facie case of obviousness with respect to Compound (1c) because the prior art provides no basis for predicting whether Compound (1c), as a structurally distinct compound, would achieve a similar binding constant or degree of stabilization in a Captisol® complex. Applicant argues in Section II of the Response, Structural Differences Between Compound (1c) and Melphalan Render CD Stabilization Unpredictable, that the ability of a CD to shield the nitrogen mustard group is critical to enhancing the stability of melphalan, citing with Singh reference. Applicant asserts that compound (1c) also degrades through a hydrolysis pathway with the mono-hydrolysis product being the main degradant, citing the present Specification at paragraph [167]. Applicant contends that therefore, to enhance the aqueous stability of Compound (1c) the nitrogen mustard must similarly be protected by the CD. Applicant notes the structural differences between compound 1c and melphalan. Applicant further refers to the Aiassa reference, that "interaction and/or inclusion of drug labile groups in the supramolecular complex is required for improving drug stability." Applicant argues that given the distinct three-dimensional architecture of Compound (1c), whether the nitrogen mustard arms of Compound (1c) are positioned within the Captisol® cavity in a manner that achieves this shielding cannot be predicted based on the prior art. Applicant argues in Section III of the Response, The Prior Art Provides Evidence for CD Orientation-Dependent Shielding of Compound (1c), again citing the Aiassa reference, concluding that with respect to Compound (1c) locating the nitrogen mustard at the para position rather than the meta position of the phenyl ring as in melphalan alters the geometric relationship between the aromatic insertion domain and the labile chloroethyl arms of the nitrogen mustard and that if the changed geometry leaves the nitrogen mustard arms projecting outward into the aqueous environment rather than pointing toward the interior of the CD cavity, the protective effect of CD complexation will be reduced regardless of the binding constant.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard arguments directed to structural differences between compound 1c and melphalan and the assertion that therefore to enhance the aqueous stability of Compound (1c) the nitrogen mustard must similarly be protected by the CD, it is respectfully submitted that arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). See MPEP 2145.
An argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art.
Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
Applicant further argues in Section IV of the Response, The Broader Literature Confirms the Inherent Unpredictability of Cyclodextrin Stabilization that compound (1c) also has an ortho methyl group attached to the phenyl ring that adds steric bulk on the face of the ring adjacent to the amino acid backbone and whether this improves or impairs cavity fit is inherently unpredictable without empirical measurement. Applicant asserts that the unpredictability of CD-mediated stabilization is confirmed across a wide body of literature reviewed by Aiassa et al. For example, in Table 2 of Aiassa et al. when complexed with SBE-ß-CD famotidine exhibited a destabilizing effect, in contrast to the stabilizing effects observed when the same drug was complexed with HP-β-CD or CM-β-CD. Applicant further argues that this unpredictability is demonstrated even within the melphalan system itself. Pipkin reports that free-base melphalan displayed significantly lower solubility enhancement than that provided in a prior literature report when a sulfobutyl ether ß-CD with an average degree of sulfobutylether substitution of 6.5 was used rather than one with a degree of substitution of 7A. Applicant contends that if such a small structural change in the SBE-ß- CD itself produces an unexpected effect on the solubility enhancement of melphalan, the structural differences introduced in Compound (1c), which are far more substantial, carry a commensurately greater potential to unexpectedly change the properties of the Compound (1c)/SBE-B-CD complex.
Applicant’s arguments have been fully considered but are not found to be persuasive. As set forth above, it is respectfully submitted that arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). See MPEP 2145.
An argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art.
Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
Further, see e.g. Das et al. (Indian J Pharm Sci, 2019, 81(4), 589-600), provided in response to Applicant’s arguments. Das states that SBE-β-CD is a versatile derivative of the parent β- CD. The ability to solubilize poorly soluble drugs is higher than parent β-CD due to the presence of hydrophobic butyl moiety. SBE-β-CD can be applied for use in formulation of various drug delivery systems incorporating a variety of guest molecules ranging from small molecules to large compounds, peptides and proteins. An optimised inclusion complex can be an efficient strategy to increase the solubility of poorly soluble compounds and provide stability to a large number of active pharmaceutical ingredients. Being able to be produced from extremely simple processes, SBE-β-CD inclusion complexes can be a viable technique to reduce the dose of the drug candidates and thereby possibly reducing the occurrence of drug related toxicities. Accordingly, as SBE-β-CD as SBE-β-CD can be applied for use in formulation of various drug delivery systems incorporating a variety of guest molecules ranging from small molecules to large compounds, peptides and proteins, it is considered that it is not necessarily unexpected that compounds which vary by only two methyl moieties, as compound 1c and melphalan, may exhibit solubilization by SBE-β-CD.
Applicant argues in Section V of the Response, Experimental Stability Data Confirm the Unpredictable Interaction Between Compound (1c) and Melphalan and SBE-β-CD, citing Example 9 and data set forth therein. Applicant notes that when formulated as the HCl salt in Captisol®, Compound (1c). HCl achieved 97% stability at both 0.5 and 2.0 hours, matching that for melphalan-HCl at 0.5 hours and exceeding it at 2.0 hours (97% VS. 92%). As free bases in Captisol®, the two compounds performed comparably, with Compound (1c) free base retaining 94% at 0.5 hours and 84% at 2.0 hours, versus 97% and 84% for melphalan free base. Applicant notes that the Office has indicated that the difference in degradation kinetics between the Captisol@/melphalan:HCI and Captisol®/ Compound (1c). HCI formulations is not meaningful and asserts that this position, however, misconstrues Applicant's argument. The Applicant is not relying on superior results in the Captisol® formulation to rebut a prima facie case of obviousness. Rather, Applicant asserts that the Office has not established a prima facie case of obviousness in the first instance. Applicant argues that the relevant inquiry, therefore, is not whether Compound (1c) performs better than melphalan-F in Captisol® or exhibits some superior property with respect to melphalan-H in Captisol®, but whether a person of ordinary skill in the art would have had a reasonable expectation of success in predicting before making and testing a Captisol® formulation, that Compound (1c). HCl a compound with materially different three-dimensional structure than melphalan-HCI would achieve adequate stability in a Captisol® complex. Applicant contends that because the binding constant of Compound (1c) with Captisol® was not established by the prior art and has not been directly measured, and because the prior art cited by the Office, i.e., Pipkin and Jandeleit and further supported by the documents cited herein, demonstrates that even minor structural changes can alter binding constants by orders of magnitude, the prior art does not provide a basis for a person of ordinary skill to predict that Compound (1c) would achieve the 97% stability observed at 2.0 hours.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that it is well shown from the prior art as a whole that SBE-β-CD can be applied for use in formulation of various drug delivery systems incorporating a variety of guest molecules ranging from small molecules to large compounds, peptides and proteins, it is considered that it is not necessarily unexpected that compounds which vary by two methyl moieties, as compound 1c and melphalan, may exhibit solubilization by SBE-β-CD. 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. Further, with regard to 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)-HCI, and that the superior stability of the Compound (1c)-HCI / SBE6.5-B-CD complex compared to other stability-promoting formulations represents an unexpected result in view of Jandeleit and Pipkin.
example, see Singh et al. (Pharm Dev Technol, 2018, 23(10), p. 1024-1029), provided by Applicant. For example, Singh shows that formulation of structurally similar melphalan with Captisol technology also significantly improved stability compared to melphalan hydrochloride reconstituted with propylene-glycol based diluents.
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 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-ß-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-ß-CDs have been reported to enhance stability of many drugs compared to other CDs. 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'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
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