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 the Claims
Acknowledgement is made of the response filed on August 24, 2026. In that response, claims 14 and 15 were amended and claims 21-30 were added. Withdrawn claims 1-13 and 16-20 were cancelled. Claims 14, 15, and 21-30 are treated on the merits in this action. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Objections
Claims 14, 15, 25, and 30 are objected to because of the following informalities: “Next generation impactor” appears to be a non-trademarked term of art denoted usually as “Next Generation Impactor” or “next generation impactor”. Appropriate correction is required.
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.
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.
Claim(s) 14, 15, and 21-30 are rejected under 35 U.S.C. 103 as being unpatentable over Brudnicki (US 2020/0022917) in view of DeHaan (US 2015/0136130).
Brudnicki teaches preparing a powder form of a therapeutic agent, e.g., aflibercept, bevacizumab, or a “small molecule VEGF antagonist” angiogenesis inhibitor (paras.0076, 0082, 0098, 0104; see entire document including title; abstract; paras.0001, 0008-09, 0019, 0046-50,0055-56, 0061-63, 0083-84, 0102, 0104-05, 0120-22, 0131). “In one aspect, the invention provides a method of manufacturing the subject formulated pharmaceutical powder by ‘spray drying’ the precursor aqueous solution containing the subject protein and any additional excipients” (para. 0112). The precursor solution comprises the active agent, thermal stabilizers such as trehalose and isoleucine, and butter (see, e.g., Table 2 pp. 7-8). “[T]he formulated pharmaceutical powder is formed by subjecting the subject feedstock to atomization to form a mist of atomized droplets, and then applying heat to the mist of atomized droplets to form the formulated pharmaceutical powder comprising the protein.” (Para. 0114; see para. 0138). The formulations “remain stable and biologically active at ambient and physiological temperatures for an extended period of time” (para. 0001).
The inlet and the outlet temperatures for the spray dryer chamber, and the spray or drying gas, are such that the feedstock solution forms a powder (para.0113; see paras. 0138, 0142, 0144, Examples 1, 3, 4). The inlet temperature is about 100 °C to 130 °C and the outlet temperature is about 55 °C, which are within the range in claims 14 and 15 (para.0113; see para.0012). The nozzle pressure is about 35-100 psi or about 2.4-6.9 bar, e.g., 2.4 bar (para.0113), within the range in claims 14, 15, 24, and 29.
For the small molecular active pharmaceutical ingredient, Brudnicki expressly teaches suitable active agents include “small molecules that inhibit VEGF - stimulated tyrosine kinases, including for example lapatinib, sunitinib, sorafenib, axitinib, and paxopanib” (para.0098; see para.0104).
Brudnicki using thermal stabilizers of “small molecules (≤ 200 grams per mole)”, including leucine, tryptophan, etc. (para.0061; see paras.0059) which are also therapeutic active pharmaceutical ingredients. Other stabilizers include trehalose which is a preferred large molecule stabilizer (paras. 0055, 0060). Brudnicki teaches the specific combination of mannitol with isoleucine or proline (claims 9, 22, 36; para. 0122). Applicant describes mannitol as a “stabilizer” and isoleucine as a “dispersant”, respectively (paras. 0174, 0182, pre-grant publication US 2024/0197628). The weight ratio of a protein drug to thermal stabilizer is 5:2-100:1 (paras. 0057, 0072; see Tables 1-3). Phosphate buffers may be used (para.0123).
The “majority of the protein microparticles of the powder have a diameter less than 10 microns as determined by MFI”, e.g., “1-9 µm” (para.0032; see paras. 0033-34, 0139). Therefore “the atomizing nozzle is selected to produce particles …500 nm and 5 µm” with d90 under 50 microns in claims 23 and 28. The Microflow Imaging of MFI is not expected to result in a particle size measurement that is significantly different from a next generation impactor. Furthermore the microparticle size can be controlled as the “concentration of protein as well as the total solute concentration in the feedstock may affect the size of the resultant powder constituent protein microparticle” (para.0102). The range of “less than 10 microns” overlaps the range in claims 25 and 30. For result-effective variables, in the case where claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. MPEP § 2144.05 (citations omitted). Furthermore, optimization within prior art conditions or through routine experimentation does not support patentability absent comparative evidence of criticality of the claimed range. See MPEP § 2144.05 (II) (citations omitted).
Brudnicki does not specifically disclose a process wherein the feedstock solution(s) comprises both the angiogenesis inhibitor such as bevacizumab in combination with one of the small molecule API and L-leucine in claims 14 and 15, and the crystallinity and amorphous state of the components in the spray dried particles as in claims 14-30.
DeHaan teaches respirable dry particles that contain at least one therapeutic agent such as the bevacizumab (title; abstract; paras. [0150], [0299]) and cisplatin (paras. [0151], [0176]). DeHaan teaches that the powders can be fabricated with a preselected size distribution such as 0.1-3 microns “Volume median geometric diameter” (VMGD) (para. [0193]). DeHaan teaches spray drying (paras. [0180], [0383]).
The total content of the therapeutic agent or agents in the respirable dry powder is at least 20%, at least 25%, at least 35%, at least 50%, at least 65% or at least 80% by weight (para. [0012]). DeHaan teaches excipients such as trehalose and L-leucine (paras. [0034], [0164], [0166], [0382]). The excipients may be present in amounts such as less than 90%, 80%, 70%, 60%, 50%, 40% and 25% (para. [0168]) or at 1-30% w/w (para. [0330]). DeHaan teaches the inclusion of a metal cation salt (para. [0008]) such as sodium phosphate and potassium phosphate (paras. [0066], [0067]) where the cation salt is present at about 3% by weight or 5% by weight (para. [0012]). The phosphate salts mentioned are buffers in solution.
Furthermore the excipient and pharmaceutically therapeutic agent can independently be crystalline or amorphous or present in a combination of these forms (para. [0259]). Specifically, “the crystalline phase (e.g., crystalline sodium chloride) can contribute to the stability of the dry particle in the dry state and to the dispersibility characteristics, whereas the amorphous phase (e.g., amorphous therapeutic agent and/or excipient) can facilitate rapid water uptake and dissolution of the particle upon deposition in the respiratory tract” (para. 0260).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date to combine the teachings of Brudnicki and DeHaan as recited in the instant claim(s). The skilled person would have been motivated to do so because both are drawn to spray dried pharmaceutical particles comprising active agents such as bevacizumab. Moreover the “expectation of some advantage is the strongest rationale for combining references”. MPEP § 2144(II). “Because the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves.” MPEP § 2144(II) (citations omitted). Here DeHaan teaches suitable active agents and excipients and their concentration ranges which the skilled person could optimize, along with process variable such as the nozzle pressure, to obtain the particle sizes desired.
Brudnicki does not specifically disclose preparing separate solutions of an angiogenesis inhibitor protein and a small molecular active agent as in claim 15. However making separable what was known in the prior art where removability or access was desirable, has been held to be obvious. See MPEP § 2144.04 (V)(C) (citations omitted). Here the skilled person would have recognize that “small molecules … for example lapatinib, sunitinib, sorafenib, axitinib, and paxopanib” and “[m]acromolecular inhibitors …bevacizumab , the Fab fragment ranibizumab, the trap aflibercept[sic], and the PEGylated aptamer pegaptanib” could require different solvents for optimal feedstock solution for spray drying. Therefore preparing separate spray drying solutions by dissolution of the small active agent in a first solvent and another solution by dissolution of the angiogenesis inhibitor would have been prima facie obvious to one of ordinary skill in the art.
Response to Arguments
Applicant’s arguments with respect to claim(s) 14, 15, and 21-30 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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 14, 15, and 21-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34 and 35 (09/18/2026) of copending Application No. 18/253,190 (reference application) in view of Brudnicki (US 2020/0022917).
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to identical spray drying process comprising steps (a) through (d) comprising overlapping concentration ranges for each of the active agents, L-leucine, and trehalose. The difference is that the present claims recite spray drying process conditions, which Brudnicki teaches specifically. The ‘190 application’s claims require bevacizumab; however it is an angiogenesis inhibitor. The ‘190 application’s claims further recite “wherein the bevacizumab and the trehalose are molecularly dispersed and not phase separated” and a fine particle fraction which render the claims narrower. Therefore the ‘190 application’s claims anticipate the present claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants requested reconsideration of the double patenting rejection(s) in light of the amendments and requested that the provisional rejection(s) be held in abeyance. (Remarks, 8, August 24, 2026.)
The provisional double patenting rejection is maintained for the reasons discussed herein. It will be maintained until Applicant submits properly executed terminal disclaimer or arguments that effectively overcome the rejection.
CONCLUSION
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to H. S. PARK whose telephone number is (571)270-5258. The examiner can normally be reached on weekdays.
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/H. SARAH PARK/Primary Examiner, Art Unit 1614
