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 .
Detailed Action
This office action is in response to applicant’s communication filed on 7/6/26.
Claims 1-15 and 21-25 are pending in this application. Claims 12-15 and 21-25 have been withdrawn. Claims 1-11 are being examined in this Office Action.
The 103 rejection is maintained. It relies on the same references as the Office action mailed 4/6/26, except Wang, which is no longer needed.
Claim Rejections – 35 USC 103
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 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.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148
USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 1 03(a) are summarized as follows:
Applicant Claims
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue, and resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-11 remain rejected under 35 U.S.C. 103 as being unpatentable over Zeng et al. (US 20130035483, pub date Feb. 7, 2013, applicant’s IDS filed 12/10/23), in view of Nakagawa et al. (US 20160158228, pub date June 9, 2016, applicant’s IDS filed 12/10/23), further in view of Viswanath et al. (US 20080091008, pub date April 17, 2008, applicant’s IDS filed 12/10/23).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Zeng et al. teaches a method to convert amorphous everolimus to crystalline everolimus (abstract; paragraphs 4, 21, 28). A slurry of the amorphous drug is formed in a solvent. The slurry is aged, or incubated, so the amorphous drug converts to crystals (paragraphs 6-10, 30, 38).
Zeng et al. teaches that seed crystals of the crystalline drug may be added to the slurry to speed conversion. This reads on a nucleation initiator. The seeds grow as the amorphous drug dissolves. Over time, the amorphous drug is replaced with crystalline drug (paragraph 35). Seeds of a desired crystal form give better control of the form made (paragraph 36).
Zeng et al. teaches crystals with a size of about 20 µm to about 10 nm. The size may be set by sonication during aging (paragraph 46). Example 7 gives a micro-crystalline product (paragraph 55). Thus, Zeng et al. teaches drug microcrystals.
Zeng et al. teaches mixed solvents, such as heptane/ethyl acetate. The volume ratio of the aliphatic hydrocarbon to the ester cosolvent is about 40:1 to about 5:1 (paragraph 33). This is an ethyl acetate to heptane ratio of about 1:40 to 1:5. Zeng et al. exemplifies a 1:20 ethyl acetate:heptane slurry (Table 2, Examples 1 and 2). The solvent blend gives a balance between conversion speed and saturation (paragraph 33). The choice of solvent is not critical (paragraph 32).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Zeng et al. is deficient in the sense that it does not teach a surfactant solution, or adding it to the drug mixture. This is cured by Nakagawa et al. and Viswanath et al.
Zeng et al. also does not state that the seeds are first mixed with a portion of the solvent. This would be obvious, as set forth below.
Nakagawa et al. teaches a process to crystallize a drug. A water solution of a surfactant and a buffer is prepared as a “crystallizing agent” (paragraph 151). A solution of the drug is then added to the crystallizing agent, and the drug crystallizes (paragraphs 154-155). The surfactant may be added to the crystallizing agent, the drug solution, or both (paragraph 152). The drug may be dissolved with the surfactant in water, an organic solvent, or a mix of both (paragraph 146). The surfactant includes polysorbate 80 and polysorbate 20. Polysorbate 80 is preferred (paragraphs 146, 152).
Viswanath et al. teaches methods to make crystalline forms of rapamycin analogs from the amorphous form (abstract; paragraphs 169, 172, 177-178). The amorphous drug is seeded with crystals of the drug (paragraphs 173, 178; Examples 23-30, paragraphs 286-293). A small crystal form of the drug can be used as a nucleation promoter. Nanometer-sized crystals, or larger particles, may be added (paragraphs 97, 157).
Viswanath et al. teaches “The presence of surfactant-like molecules in the crystallization vessel may influence the crystal nucleation and selectively drive the growth of distinct polymorphic forms. Thus, surfactant-like molecules can be introduced into the crystallization vessel either by pre-treating or by direct addition to the crystallization medium.” (paragraph 96)
Viswanath et al. also teaches “nucleation can be controlled by adjusting the interfacial tension of the crystallizing medium by introducing surfactant-like molecules either by pre-treating the crystallization chamber or by direct addition. The nucleation effect of surfactant molecules is dependent on their concentration and thus this parameter should be carefully controlled.” (paragraph 156)
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Therefore, it would be prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to add a surfactant to Zeng et al.’s seeded slurry of amorphous everolimus. Viswanath et al. teaches that surfactants influence crystal nucleation and growth. It also teaches that they may be added directly to the crystallization medium (paragraphs 96, 156). Nakagawa et al. teaches preparing a separate surfactant solution, and crystallizing the drug in its presence (paragraphs 151-155).
There would be a reasonable expectation of success. Zeng et al.’s slurry process already converts amorphous everolimus to crystals in a 1:20 ethyl acetate/heptane solvent (Table 2, Examples 1 and 2). Zeng et al. teaches seeding this slurry (paragraph 35), and teaches crystals of micrometer size or smaller (paragraphs 46, 55). Viswanath et al. teaches that surfactants act on the same nucleation step for rapamycin analogs. Zeng et al. teaches that everolimus and rapamycin are drugs of the same class (paragraphs 4, 27). Nakagawa et al. shows that a drug crystallizes in the presence of a surfactant solution.
It would also be obvious to make the surfactant solution with a first portion of Zeng et al.’s solvent. Zeng et al. teaches that the solvent blend sets the balance between conversion speed and saturation (paragraph 33). Using the same solvent keeps this balance when the surfactant solution is added. Viswanath et al. teaches that the surfactant level “should be carefully controlled” (paragraph 156). A surfactant solution of known strength gives this control. Nakagawa et al. teaches that the surfactant may be used in an organic solvent (paragraph 146).
It would also be obvious to use drug microcrystals as the seeds. Zeng et al. teaches seed crystals of the crystalline drug, and teaches everolimus microcrystals (paragraphs 35, 46, 55). Viswanath et al. teaches small crystals, including nanometer-sized crystals, as seeds (paragraphs 97, 157). It would also be obvious to add the seeds with a second portion of the same solvent. This is simply a way to add the seeds to the slurry, as taught by Zeng et al. (paragraph 35).
With regard to the order of steps in claim 1, Viswanath et al. teaches adding the surfactant “by direct addition to the crystallization medium” (paragraph 96). In the combination, the crystallization medium is Zeng et al.’s seeded slurry of amorphous drug. Thus, adding the surfactant by direct addition adds it to a formed drug mixture. In addition, the claimed steps only set the order in which the same ingredients are mixed. The end mixture is the same: solvent, surfactant, seed microcrystals and amorphous drug. The selection of any order of mixing ingredients is prima facie obvious. In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930). The selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959); MPEP 2144.04 IV.C.
Applicant’s specification does not make the order critical. It states that changes may be made in the “arrangement of steps” (paragraph 65). It describes mixing the nucleation initiator “with the surfactant solution and with an amorphous form of a drug” in no set order (paragraphs 36, 43). The record has no unexpected results for the claimed order.
Claims 2-7: Zeng et al. teaches heptane, ethyl acetate, and mixes of both (paragraph 33). Zeng et al.’s ratio of about 1:40 to 1:5 overlaps the claimed ranges of about 1:4 to 1:30 and about 1:4 to 1:20. Zeng et al. exemplifies the 1:20 ratio of claim 7 (Table 2, Examples 1 and 2). In the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); MPEP 2144.05 I. As discussed above, it would be obvious to use this same solvent for both the surfactant solution and the nucleation initiator solution.
Claims 8 and 9: Nakagawa et al. teaches polysorbate 20 and polysorbate 80 (paragraphs 146, 152). The specification equates the surfactant of claim 8 with TWEEN 20 (polysorbate 20), and the surfactant of claim 9 with TWEEN 80 (polysorbate 80) (paragraph 41). If claim 8 is instead read by its chemical name, it is polysorbate 80, which Nakagawa et al. also teaches. Thus, Nakagawa et al. teaches the surfactants of claims 8 and 9. The selection of a known material based on its suitability for its intended use supports a prima facie case of obviousness. Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945); MPEP 2144.07.
Claims 10 and 11: Zeng et al. teaches amorphous everolimus and seed crystals of the crystalline drug form (paragraphs 28, 35). Thus, it would be obvious to use everolimus microcrystals as the seeds and amorphous everolimus particles as the drug, as discussed above.
Response to Arguments
Applicant’s arguments have been considered but are not persuasive for the following reasons:
Applicant argues that the art gives no reasoned basis, and no reasonable expectation of success, for the claimed combination and sequence (citing In re Cyclobenzaprine and OSI Pharm.).
The examiner does not agree. The rejection gives reasons. Viswanath et al. teaches that surfactants affect nucleation and may be added directly to the crystallization medium (paragraphs 96, 156). Zeng et al. converts amorphous everolimus to crystals in a 1:20 ethyl acetate/heptane slurry (Table 2, Examples 1 and 2). It teaches seeding the slurry and teaches microcrystals (paragraphs 35, 46, 55). Nakagawa et al. makes a separate surfactant solution and crystallizes a drug in its presence (paragraphs 151-155). Only a reasonable expectation of success is required, not absolute predictability.
Zeng et al.’s base process works. One would expect it to still form crystals when a surfactant is added for the purpose taught by Viswanath et al. Also, the rejection does not rest on an “obvious to try” rationale, so applicant’s point about a finite number of solutions under KSR does not apply. It rests on express teachings in the references, and on the known obviousness of changing the order of mixing.
Applicant argues that Viswanath states, at paragraph 4, that control of nucleation, growth, dissolution, and morphology “remains primarily a matter of ‘mix and try.’”
This is not persuasive. Paragraph 4 is background. It describes the field before Viswanath et al.’s own teachings. Viswanath et al. then gives specific guidance. It teaches adding surfactant by pre-treating or by direct addition, and controlling its level (paragraphs 96, 156). It teaches seeding with small crystals (paragraphs 97, 157). Also, claim 1 does not require any crystal form, habit, or size, other than “microcrystals.” The art teaches microcrystals (Zeng et al., paragraphs 46, 55).
Applicant argues that the order of addition is not an arbitrary detail. Applicant states that it affects nucleation density, crystal growth, aggregation, morphology, and particle size.
This is not persuasive. This is attorney argument. No data or declaration is of record. Attorney argument cannot take the place of evidence. In re Pearson, 494 F.2d 1399, 1405, 181 USPQ 641, 646 (CCPA 1974); MPEP 716.01(c).
The specification does not show that the order is critical. It states that changes may be made in the “arrangement of steps” (paragraph 65). It describes mixing the nucleation initiator “with the surfactant solution and with an amorphous form of a drug” in no set order (paragraphs 36, 43). Only one order is exemplified, with no comparison (paragraphs 49-58). Also, Viswanath et al. teaches direct addition of the surfactant to the crystallization medium (paragraph 96). Thus, the claimed order is taught. To show that the order is critical, applicant may submit a declaration under 37 CFR 1.132. The data should compare the claimed order to other orders, and be commensurate in scope with the claims.
Applicant argues that Nakagawa concerns a different drug and an injectable aqueous process, and that Wang concerns drug coatings for medical devices.
This is not persuasive. Nakagawa et al. is relied on for making a surfactant solution and combining it with a drug to crystallize the drug. It is also relied on for polysorbate 20 and polysorbate 80 (paragraphs 146, 151-155). Nakagawa et al. is analogous art. It is in the same field of endeavor, making crystals of a drug. It is also reasonably pertinent to the problem applicant faced: crystallizing a drug in the presence of a surfactant.
One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Wang is no longer relied on in the 103 rejection, since Nakagawa et al. teaches both polysorbates. The rejection now relies on fewer references, with the same basis. This is not a new ground of rejection. In re Kronig, 539 F.2d 1300, 190 USPQ 425 (CCPA 1976). Thus, the argument about Wang is moot.
Applicant argues that no reference teaches first preparing a nucleation initiator solution from drug microcrystals, mixing it with amorphous drug particles, and only then adding a separately prepared surfactant solution.
This is not persuasive. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. Zeng et al. adds seed crystals to a slurry of amorphous drug (paragraph 35). Viswanath et al. teaches small crystals as seeds (paragraphs 97, 157). It teaches direct addition of the surfactant to the crystallization medium (paragraph 96). Nakagawa et al. teaches a separately prepared surfactant solution (paragraphs 151-154). Together, these teach the claimed steps, for the reasons set forth above.
Applicant argues that the rejection uses impermissible hindsight.
This is not persuasive. Any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Each step relied on above is taken from Zeng et al., Viswanath et al., or Nakagawa et al.
Applicant also cites In re Cyclobenzaprine, OSI Pharm., Leo Pharm. and Sanofi-Synthelabo. These cases are not on point. In each case, the finding rested on record evidence of unpredictability or unexpected results, such as test data or expert testimony. No such evidence is of record here.
Conclusion
No claim is 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 extension fee 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 Jennifer Cho Sawyer whose telephone number is (571) 270 1690. The examiner can normally be reached on Monday-Friday 9 AM - 6 PM PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-274-1690.
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/JENNIFER C SAWYER/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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