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 .
Claim Status
Claims 1-14 are pending.
Priority
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The foreign priority document is not in English. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Consequently, the effective filing date for application of art is December 30, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/5/23 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 14 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maniar (WO9214449).
Applicant claims:
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Regarding claim 14, Maniar disclose a protein delivery microparticle, which are produced by spray drying method to produce an average particle size of less than 250 microns (Page 8, Example 3) that is reasonable interpreted to be micron sized spherical particles and reads on the claimed protein microbeads, which are just easy to handle, dried solid micron-sized spheres (Specification, page 3, lines 60-61), comprising biologically active protein or peptide (Claim 1) with a stabilizer (Claim 3) where the protein is selected from the group of biologically active proteins, protein fragments, and peptides, which are naturally occurring, recombinantly engineered, or synthetically produced (Claim 5). The stabilized protein microparticles of Maniar inherently have a reversibility of 90% to 100% and possess stability against physical shocks or high temperature stress of 40°C to 70°C. The Examiner's finding is based on the principle that products of identical chemical compositions cannot have mutually exclusive properties. This is a well settled principle in patent law. See In re Papesch, 315 F.2d 381,391 (CCPA 1963) ("From the standpoint of patent law, a compound and all of its properties are inseparable; they are one and the same thing."). Once a prima facie case of anticipation has been established, the burden shifts to the Appellants to prove that the prior art product does not necessarily or inherently possess the characteristics of the claimed product. See In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (“Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product.”). Whether the rejection is based on "inherency" under 35 U.S.C. § 102, on "prima facie obviousness" under 35 U.S.C. § 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO' s inability to manufacture products or to obtain and compare prior art products. In re Best, 562 F.2d 1252, 1255 (CCPA 1977). See MPEP 2112(V).
With respect to the USC 102 rejection above, please note that in product-by-process claims, “once a product appearing to be substantially identical is found and a 35 U.S.C. 102/103 rejection [is] made, the burden shifts to the applicant to show an unobvious difference.” See MPEP 2113 Product-by-Process Claims [R-08.2017]
I. PRODUCT-BY-PROCESS CLAIMS ARE NOT LIMITED TO THE MANIPULATIONS OF THE RECITED STEPS, ONLY THE STRUCTURE IMPLIED BY THE STEPS
“[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
As a practical matter, the Patent Office is not equipped to manufacture products by the myriad number of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
Claim(s) 1-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al. (International Journal of Biological Macromolecules 2021;185:935-948; published online July 05, 2021).
Regarding claims 1 and 14, Kim et al. disclose protein microbeadification in two methods where in the non-SPG method:
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(Figure 1); and in the SPG method utilized the immunogenic protein IgG and trehalose (Abstract; Figure 4):
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(Figure 2), where “vortexing” is interpreted to be a form of stirring, to produce protein microbeads as shown in Figure 2:
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Kim et al. report the reversibility of the IgG microbeads with trehalose was over 99% and that the formulation was highly stable under repeated mechanical shocks and at an elevated temperature (Abstract). Kim et al. also disclose: “To collect the precipitants, the emulsion was centrifuged at 10,000 rpm for 2 min.” (Page 936, bottom right column). Consequently, Kim et al. disclose a method of stirring an emulsion prepared by mixing protein with a process stabilizer trehalose in an organic solvent octanol to dehydrate the protein, centrifuging the precipitate formed by stirring the emulsion and dehydrating the protein and drying after removing the supernatant.
Regarding claims 3-5, Kim et al. disclose the organic solvent as n-octanol (Figure 2).
Regarding claims 6-7, Kim et al. disclose the process stabilizer as trehalose (Abstract; Figure 4).
Regarding claim 8, Kim et al. emulsifying through a SPG membrane thereby enabling uniformity in particle shape and size of the protein microbeads (Figure 2).
Regarding claims 9-10 and 14, Kim et al. report the reversibility of the IgG microbeads with trehalose was over 99% and that the formulation was highly stable under repeated mechanical shocks and at an elevated temperature (Abstract). It is inherent in the microbeads of Kim et al. to have a stability against high temperature of 40-70°C.
Regarding claim 11, Kim et al. report the dehydration step of 10 minutes (Figure 10), which falls within the range of 10 seconds to 20 minutes. See MPEP 2132.03(I).
Regarding claim 12, Kim et al. report that the initial vacuum pressure was set at 57 mTorr at 25 ◦C for 48 h and later, it was adjusted to 200 mTorr at 35 ◦C for 48 h (Page 937, top left column).
Regarding claim 13, Kim et al. report the protein microbeads as a powder (Page 946, left column last sentence), which is a formulated form for inhalants or topical formulations.
Claim 14 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Feng et al. (WO2017173068).
Regarding claim 14, Feng et al. disclose a microbead comprising a therapeutic agent, mannitol, trehalose or sucrose (Claims 1-3, 5, 6 and 13), where the therapeutic agent comprises a protein or peptide or antibody (Claims 10-12). Thus, Feng et al. disclose protein microbeads with the same process stabilizers as instantly claimed. Therefore, the same reversibility of 90-100% and stability against physical shocks or high temperature stress of 40-70°C is inherent in the protein microbead of Feng et al. See the Examiner’s discussion of product-by-process and inherency above, which is incorporated here by reference.
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, 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. 103(a) 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.
Claims 1-7 and 9-14 are rejected under 35 U.S.C. 103(a) as being unpatentable over Petrel et al. (US20140288282).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Applicant claims, for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a therapeutic protein formulation research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from therapeutic protein formulation methods and techniques— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1 and 14, Petrel et al. teach processes for producing protein microparticles (Title), which are reasonably interpreted to read on protein microbeads, where a protein solution is atomized and collected in a dehydration solvent that is being mixed (Abstract; claim 1) by vortexing (Claim 17), which is interpreted to be a form of stirring, and evaporating the solvent obtain the protein microparticles (Claims 2-9 and 25; Figure 6 showing spherical beads; see also [0037]) that retain at least 90% of their original specific activity (Claim 19). The “emulsion” limitation is met by mixing the protein with the organic solvent (step (a) of claim 1). Petrel et al. teach centrifugation to isolate/separate the particles by removing the supernatant, which reads on step (b) of claim 1, and solvent removal by evaporation that inherently dries the protein microbeads [0047, 0065], or spray-drying/atomization (Claim 18; [0041]), also removes solvent and dries the protein microbeads, which renders obvious step (c) of claim 1. Dry protein microparticles are taught [0051]. Petrel et al. also teach: “in the present disclosure the protein can be dissolved, emulsified, suspended, dispersed, or otherwise combined with the liquid to form the protein solution.”
Regarding claim 2, Petrel et al. teach: “The term "protein" refers to a sequence of amino acids that is of sufficient chain length to produce a tertiary or quaternary structure. Examples of proteins include monoclonal antibodies, insulin, human
growth hormone, and erythropoietin.” [0040].
Regarding claims 3-5, Petrel et al. teach using n-decanol (Claim 13; [0011, 0043, 0064-0065]) but can be a linear or branched alcohol with 4 to about 12 carbon atoms [0043], which includes n-octanol. Solvents can also be ethanol, pentanes, hexanes, ethers, chlorocarbons, ethylacetate, fluorocarbons, isopropanol, or tetrahydrofuran (THF). Generally, a suitable secondary solvent is one with high vapor pressure and in which the protein has poor solubility. [0047].
Regarding claims 1, 6, 7 and 14, Petrel et al. teach that while no such excipients are needed, smaller amounts of the process stabilizers trehalose or sucrose can be used [0052]. Petrel et al. teach: “Stabilizing excipients known in the art may also be included in either the protein solution or the dehydration solvent to afford further desirable properties in the resultant microparticles.” [0044].
Regarding claim 13, Petrel et al. teach formulation for drug delivery by injection [0003] and that solid particles are obtained [0004], which given their size are of a formulation form for inhalants or topical formulations.
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
1. The difference between the instant application and Petrel et al. is that Petrel et al. do not expressly teach a process that produces protein microbeads wherein the protein microbeads have a reversibility of 90% to 100%, and possess stability against physical shocks or high temperature stress of 40°C to 70°C. However, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to measure the reversibility and stability against physical shocks or high temperatures of the protein microparticles of Petrel et al, and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because these parameters appear to be intrinsic to the protein microparticles of Petrel et al. where nearly 100% of the original GOX specific activity was retained (Figure 7; [00290065] and the protein microparticles retain at least 90% of their original specific activity (Claims 4 and 19), which appears to be an indirect measurement of reversibility. Formulations of proteins with the same process stabilizers as claimed by Applicant naturally results in a stabilized protein microparticle formulation that possesses stability against physical shocks or high temperature stress of 40°C to 70°C in the absence of evidence to the contrary.
The difference between the instant application and Petrel et al. is that Petrel et al. do not expressly teach a process wherein the dehydration in the step (a) is performed for 10 seconds to 20 minutes and wherein the drying in the step (c) is performed at 25°C to 40°C for 24 to 130 hours under a pressure of 50 mTorr to 300 mTorr. However, the artisan would optimize the dehydration time to ensure the protein is properly dehydrated and while Petrel et al. teach evaporation of the solvent under nitrogen gas [0065], traditional freeze-drying (lyophilization) to produce protein microparticles is well-known to the ordinary artisan [0003, 0052] and thus determination of the temperature, time period and pressure of 25°C to 40°C for 24 to 130 hours under a pressure of 50 mTorr to 300 mTorr to perform the freeze-drying method is routine laboratory skill for the ordinary artisan.
Claim 8 is rejected under 35 U.S.C. 103(a) as being unpatentable over Petrel et al. (US20140288282), as applied to claims 1-7 and 9-14 above, in further view of Sihan et al. (Scientific Reports 2016;6:26407: 7 pages) and Yedomon et al. (European Journal of Pharmaceutics and Biopharmaceutics 2013;85:398-405) and Joseph et al. (European Journal of Pharmaceutics and Biopharmaceutics 87 (2014) 178–186) and Vladisavljevic et al. (Microfluid Nanofluid (2012) 13:151–178).
Applicant claims:’
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Determination of the scope and content of the prior art
(MPEP 2141.01)
The reference of Petrel et al. is discussed in detail above and that discussion is incorporated by reference.
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
The difference between the instant application and Petrel et al. is that Petrel et al. do not expressly teach a process wherein the step (a) further comprises emulsifying the protein through a Shirasu porous glass (SPG) membrane or a microchip prior to stirring the emulsion, thereby enabling uniformity in particle shape and size of the protein microbeads. However, Petrel et al. is open to other processes such as emulsification to make the protein solution [0040]. In this regard, Sihan et al. teach using microchips to make uniform droplets (Figure 1) and cites Saito et al. for preparing monodisperse emulsions with straight-through microchannels when using bovine serum albumin (BSA), β-lactoglobulin (β-lac), soybean flour, and whey protein (Page 2, first paragraph). Thus, using microchips for the protein emulsification process is well-known to the ordinary artisan and another means to achieve the end-goal of Petrel et al. The ordinary artisan would employ microchips with a reasonable expectation of success in achieving uniformity in particle shape and size of the protein microbeads. Moreover, it is known through the teachings of Yedomon et al. to employ Shirasu Porous Glass membrane technology to obtain protein particles on a large scale (Abstract; Figure 1) where it is a relatively simple technique to produce large volumes of colloidal dispersions (Page 399, left column 3rd paragraph; Figure 10) and as an alternative to emulsification and desolvation (Introduction right column 2nd paragraph). In addition, Joseph et al. teach that: “Homogenization generates high shear forces and may thus not be suitable for the processing of sensitive pharmaceutical ingredients, e.g., proteins.” To get around this, Joseph et al. teach employing Shirasu Porous Glass membrane emulsification because “the comparatively lower process pressures of at maximum 10 bar SPG membrane emulsification is an interesting alternative method to high-pressure homogenization.“ (Abstract; Figures 1-2; Table 1; page 152, 2.1 Direct Membrane emulsification; 2.2 Premix membrane emulsification). Vladisavljevic´ et al. also teach that SPG membrane is the most commonly used membrane in ME (Page 154, 2.3 Choice of membrane for ME but also see the Abstract and Figures 1-2). Consequently, it is desirable to employ Shirasu Porous Glass membrane, which is the most commonly used membrane in ME, for emulsification for proteins to avoid the high-pressure homogenization that can be detrimental to sensitive proteins with a major benefit of very short preparation time and thus short stress to the dispersion (Page 185, Conclusions). The ordinary artisan would do so with a reasonable expectation of success in in achieving uniformity in particle shape and size of the protein microbeads by emulsifying the protein through a Shirasu porous glass (SPG) membrane or a microchip prior to stirring the emulsion, thereby enabling uniformity in particle shape and size of the protein microbeads after removing the supernatant by centrifuging a precipitate formed by stirring the emulsion and dehydrating the protein and drying after removing the supernatant.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613