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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/5/26 has been entered.
Claims 1-15 and 21-25 are pending in this application. Claims 12-15 were previously withdrawn. The examiner acknowledges applicant’s newly added claims 21-25, drawn to forming microcrystals with a particular morphology and configuring the microcrystals in suspension. However, since applicant has received an action on the merits for the originally presented invention, drawn a method for crystallization, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 12-15 and 21-25 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03. As a result, claims 1-11 are being examined in this Office Action.
Due to applicant’s claim amendments filed 3/5/26, the objection in the office action filed 9/24/25 is withdrawn.
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(a) as being unpatentable over Zeng et al. (US 20130035483, 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), further in view of Wang (US 20080118544, pub date May 22, 2008; mentioned by Zeng et al., applicant’s IDS filed 12/10/23).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Zeng et al. teaches conversion of an amorphous drug, everolimus, to the crystalline form of the drug, by seeding a saturated amorphous slurry, otherwise known as using a nucleation initiator, with crystalline seed crystals to speed initiation of conversion. This drug slurry is aged, or incubated, to allow the amorphous form of the drug to convert to the crystalline drug. The form of the everolimus crystalline product that was isolated was of a microcrystalline structure. (paragraphs 4, 30, 35-38, 55; Example 7)
Zeng et al. exemplifies starting with a slurry suspension of the amorphous drug (and optionally adding additional drug crystals), to grow crystals, that possess, for example, larger needles and plate like crystals (examples, paragraphs 52-55; claims 1 and 9).
Since Zeng et al. teaches seeding the slurry with the crystalline drug form of everolimus to speed initiation of conversion and the everolimus product was microcrystalline in structure, it is reasonable to expect this reads on applicant’s limitation for “everolimus drug microcrystals” (claim 10), absent evidence to the contrary. Even if it does not, it would be obvious to use the everolimus microcrystals as a nucleation initiator since Zeng et al. teaches the form of the everolimus crystalline product that was isolated was of a microcrystalline structure and the crystalline drug form are used as seed crystals, otherwise known as a nucleation initiator.
Zeng et al. teaches a skilled person can determine the particular combination of drug and solvent used (paragraph 38).
Zeng et al. also teaches the equivalency of everolimus and rapamycin (paragraph 4)
Zeng et al. teaches the use of a mixed solvent blend of heptane/ethyl acetate with a volume ratio of 40:1 to about 5:1, for slurry conversion and a balance between conversion speed and saturation excess (paragraph 33). Zeng et al. also specifically teaches the use of a 1:20 ethyl acetate/heptane solvent solution to form a slurry suspension and teaches formation of slurry suspensions by the addition of more everolimus (examples 4 and 7, paragraph 53 and 55, and Table 2).
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 applicant’s surfactant solution for crystallizing the drug. This is cured by Viswanath et al. and Nakagawa et al.
Viswanath et al. teaches methods of manufacturing crystalline forms of rapamycin analog or derivatives from an amorphous state using suspensions, with seeding/a nucleation initiator to promote crystal formation (abstract and paragraphs 157, 169, 172-178, 181).
Viswanath et al. teaches everolimus can be used as the drug, instead of rapamycin (paragraph 200).
Viswanath et al. teaches the use of surfactants in solvent solutions to promote nucleation in crystallizations. 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. Surfactant molecules can be either specifically selected or randomly screened for their influence in directing crystallization. In addition, the effect of the surfactant molecule is dependent on its concentration in the crystallization vessel and thus the concentration of the surfactant molecules should be carefully controlled” and “in some cases, direct seeding of crystallization reactions will result in an increased diversity of crystal forms being produced. In one embodiment, particles are added to the crystallization reactions. In another, nanometer-sized crystals (e.g., nanoparticles) are added to the crystallization reactions. These particles can be either nanometer sized or larger.” (paragraphs 96, 97, 156-159)
Viswanath et al. also teaches “Thus, 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)
Furthermore, Viswanath et al. also teaches “Direct seeding with a plurality of nucleation seeds of the rapamycin analog in various physical states provides a means to induce formation of different crystal forms in different compositions. (paragraph 157)
Zeng et al. and Viswanath et al. are deficient in that they do not specifically teach polyoxyethylene (80) sorbitan monooleate (polysorbate 80) or polyoxyethylene (20) sorbitan monooleate (polysorbate 20) as the surfactant used for crystallization.
Nakagawa et al. teaches the use of surfactants in a solvent solution for the process of crystallizing a drug. Nakagawa et al. teaches preparation of a solution of a surfactant, which can be added to a sterile solution of the active drug ingredient, in which preferably the surfactant is polyoxyethylene (80) sorbitan monooleate (polysorbate 80). The surfactants that can be used are polyoxyethylene (80) sorbitan monooleate (polysorbate 80) or polyoxyethylene (20) sorbitan monooleate (polysorbate 20). (paragraphs 146, 151-152 and process of crystallization steps (2) and (3)).
Nakagawa et al. teaches the equivalency of water, an organic solvent or mixtures of as the solvent. Nakagawa et al. forms a solution of the active drug and a solution of the surfactant. The surfactant can be added to the solution of the active drug. The active drug solution can also be added to the surfactant containing the crystallizing agent solution (paragraphs 146 and 151-154)
The primary reference Zeng et al. also mentions the Wang reference (US 2008/0118544) in relation to possible surfactants: “surfactants such as described in US 2008/0118544 A1”. Wang (US 2008/0118544) specifically names PEG-20 sorbitan monolaurate (Tween-20) and PEG-20 sorbitan monooleate (Tween-80), as possible surfactants, the same surfactants as in applicant’s claims 8 and 9.
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 at the time of the invention, to include Viswanath et al.’s surfactant, into Zeng et al.’s crystallization of everolimus from the amorphous form, since Viswanath et al. teaches that the presence of surfactants influences the crystal nucleation and growth of the crystal forms. There would be a reasonable expectation of success since Viswanath et al. teaches surfactants in the crystallization vessel of drugs can influence the crystal nucleation and selectively drive the growth of distinct polymorphic forms to form crystals from the amorphous form. Thus the addition of surfactants to improve crystallization of both rapamycin analogs and everolimus from the amorphous form is old in the art.
Because Zeng et al. teaches starting with a slurry suspension of the amorphous drug to grow more crystals and because Viswanath et al. teaches that the presence of surfactants influences the crystal nucleation and growth of the crystal forms, it would be prima facie obvious to one of ordinary skill in the art at the time of the invention, to form additional drug crystals by the addition of a surfactant, which would read on applicant’s new limitation in claim 1. If these teachings do not suggest applicant’s new limitation, then a 112 rejection might be necessary, since the examiner interprets applicant’s claim 1 new limitation as reading on a combination of Zeng et al.’s teaching for the growing of additional crystals that were not present in the initial drug mixture slurry with the obvious addition of Viswanath et al.’s surfactants for advantageous crystallization. Thus it would be reasonable to expect that Viswanath et al.’s surfactant would be an advantageous addition to Zeng et al.’s crystallization of a drug slurry mixture to form additional drug crystals, absent evidence to the contrary.
It would also be prima facie obvious to one of ordinary skill in the art at the time of the invention, to include Nakagawa et al.’s and Wang’s polysorbate 20 and polysorbate 80 surfactants, into Zeng et al.’s crystallization of everolimus from the amorphous form, since both Zeng et al. and Viswanath et al. teach the equivalency of everolimus and rapamycin. It would be obvious to utilize Nakagawa et al.’s and Wang’s polysorbate 20 and polysorbate 80, since Nakagawa et al. teaches these are well-known surfactants in crystallizations. The primary reference Zeng et al. mentions “surfactants such as described in US 2008/0118544 A1”. And this reference Wang (US 2008/0118544) also specifically names PEG-20 sorbitan monolaurate (Tween-20) and PEG-20 sorbitan monooleate (Tween-80), as possible surfactants, the same surfactants as in applicant’s claims 8 and 9. Thus the use of polysorbate 20 and polysorbate 80 as surfactants are well known in the art.
Additionally, since Zeng et al. teaches a 1:20 ethyl acetate/heptane solvent solution in the formation of the slurry suspension that includes seeding with a nucleation initiator, the examiner states that it would be reasonable to expect this to read on applicant’s limitation for the nucleation initiator in a solvent mixture of 1:20 ethyl acetate and heptane, since Zeng et al.’s exemplifies formation of a slurry with 1:20 ethyl acetate and heptane (example 4). Even if it does not, it would be obvious to use a range of about 1:20 ethyl acetate and heptane with the nucleation initiator to form a slurry/dispersion/suspension, since Zeng et al. teaches the use of a nucleation initiator for seeding, with an ethyl acetate and heptane mixed solvent, that has ratios between 1:5 to 1:40, specifically 1:20, in a slurry/dispersion/suspension, for conversion to the crystalline form of everolimus.
Furthermore, since Viswanath et al. teaches the use of surfactants in solvent solutions to promote nucleation in crystallizations and since Zeng et al. teaches a 1:20 ethyl acetate/heptane solvent solution for formation of the slurry suspension for crystallization, it would be obvious to use a 1:20 ethyl acetate and heptane solvent solution with the surfactant in the slurry/dispersion/suspension, for ultimate conversion to the crystalline form of everolimus, as Viswanath et al. teaches the benefits of a surfactant in a solvent solution for nucleation formation.
In addition, it would be obvious to one of ordinary skill in the art to form a surfactant solvent solution and a nucleation initiator solution containing the drug microcrystals, then adding the amorphous drug to the nucleation initiator solution containing the drug microcrystals, then adding the surfactant solvent solution to the drug solvent mixture. This is because one of ordinary skill in the art, at the time of the invention, would through routine and normal experimentation optimize the order of these steps in order to increase yields of the crystallized drug and lower impurities. Because, the art teaches the same reactants and process steps as the applicant, it would be reasonable to expect that the order of addition is an art recognized result-effective variable. Thus it would be obvious in the optimization process to optimize when to add the surfactant and drug microcrystals or amorphous drug. Note that the order of steps does not impart patentability. The applicant does not show any unusual and/or unexpected results for the limitation stated. Note also, the prior art provides the same effect desired by the applicant, the crystallization of everolimus from amorphous everolimus with microcrystalline everolimus as the initiator and a surfactant, in a solvent of 1:20 ethyl acetate and heptane.
Thus the ordering of the addition steps is an obvious optimization tool since it would be simply a matter of operator preference, especially since the same result is obtained regardless of when the step occurs. See Ex parte Rubin , 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.)). As indicated in MPEP 2144.04 IV. C., the order of prior art process steps is prima facie obvious in the absence of new or unexpected results.
It would also be obvious to use applicant’s ethyl acetate/heptane solvent mixture ratio as the solvent solution for forming both the surfactant solution and the drug solution, since Nakagawa et al. teaches the equivalency of water, an organic solvent or mixtures of, for forming the surfactant solution. Thus absent evidence to the contrary, it would be obvious to use equivalent organic solvent solutions for forming the surfactant solution, especially since Zeng et al. teaches using the same solvent mixture for forming the active drug solution, with a reasonable expectation of success. Note that an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).
Response to Arguments
Applicant’s arguments have been considered but are not persuasive for the following reasons:
The examiner acknowledges applicant’s argument that Viswanath only teaches adding surfactants to produce different polymorphic forms, not different sizes of drug crystals. Applicant also argues that paragraph 97 of Viswanath does not connect surfactants and crystal sizes and only different polymorphic forms. Applicant also argues that the combination of Viswanath and Zeng does not teach preparing a surfactant solution and then adding it to a drug mixture.
The examiner does not agree with the applicant. In response to applicant's argument against the secondary reference, Viswanath, 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. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Thus the examiner contends that combining Viswanath et al. with Zeng et al. is proper since both teach crystallizations.
Viswanath et al. teaches the use of surfactants in solvent solutions to promote nucleation in crystallizations. In paragraph 157, Viswanath et al. teaches “Direct seeding with a plurality of nucleation seeds of the rapamycin analog in various physical states provides a means to induce formation of different crystal forms in different compositions.” Thus it would be reasonable to expect that surfactants that promote nucleation would have an effect on the formation and the growth of the crystal. Furthermore, applicant’s claim 1 does not require a specific size of the crystal, but merely formation of a microcrystal, which is taught in the cited art.
Therefore, it would be prima facie obvious to one of ordinary skill in the art at the time of the invention, to include Viswanath et al.’s surfactant, into Zeng et al.’s crystallization of everolimus from the amorphous form, since Viswanath et al. teaches that the presence of surfactants influences the crystal nucleation and growth of the crystal forms. There would be a reasonable expectation of success since Viswanath et al. teaches surfactants in the crystallization vessel of drugs can influence the crystal nucleation and selectively drive the growth of distinct polymorphic forms to form crystals from the amorphous form. Thus the addition of surfactants to improve crystallization of both rapamycin analogs and everolimus from the amorphous form is old in the art.
Conclusion
No claim is allowed.
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 Cho Sawyer
Patent Examiner
Art Unit: 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691