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
Status of the Claims
Receipt of Remarks/Amendments filed on 07/20/2026 is acknowledged. Claims 1-20 are cancelled. Claims 39-40 are new. Claims 21-22, 24-25 and 36 are amended. Claims 21-40 are herein acted on the merits.
Rejections not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Modified Rejection As Necessitated by the Amendment Filed 07/20/2026
Double Patenting
Claim 39 is objected to under 37 CFR 1.75 as being a substantial duplicate of Claim 21; When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). In this instant case, amended Claim 21 and new Claim 39 are identical in the steps recited, except that Claim 21 ii) recites “(a) increases the amount of casein in the soluble fraction”, whereas Claim 39 ii) recites “(a) transfers at least part of the casein from the insoluble fraction to the soluble fraction, thereby increasing the amount of casein in the soluble fraction”. The transferring mechanism explicitly stated in Claim 39 does not materially change the scope of the claim as both claims ultimately involve the same heating step in the same range, which increases the casein in the soluble fraction.
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 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 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).
Claims 21-25, 27, 29-32, 35-36, and 38-40 are rejected under 35 U.S.C. 103(a) as being unpatentable over Nagao et al. (Agric. Biol. Chem., 52 (1), 191-200, 1988), hereinafter Nagao.
Regarding Claims 21 and 39, Nagao teaches producing bovine milk casein in E. coli cells using DNA manipulation technique (Abstract; p. 192, L. Col. 1st paragraph; Materials and Methods). Briefly, E. coli cells were transformed with the plasmids, cultured, harvested, and centrifuged to give a supernatant and precipitate (p. 192, R. Col., Expression of casein in maxicells). Fig. 2 shows additional protein bands including b-lactamase, which is expectedly expressed based on the plasmids in Fig. 1, and reads on the claimed feature of the microorganism expressing one or more host-cell proteins. Nagao teaches fractionation of cellular components by centrifugation to give a supernatant comprising the periplasmic fraction and the precipitate comprising spheroplasts, and wherein casein was exclusively found in the outer membrane fraction (precipitate), and as an aggregated form soluble in SDS but not in Triton (p. 193, L. Col., bottom paragraph and R. Col., 2nd paragraph; Fig. 6). Nagao teaches that the insoluble casein must be recovered as a precipitate by the centrifugation, and that casein is isolated by suspending the precipitate in Tris-HCl at pH 6.8 Containing glycine and SDS, and the suspension heated at 100 ˚C, after which the solubilized proteins is separated using gel electrophoresis and the proteins eluted recovering the purified casein, which also renders Claims 22, 31-32 and 39 obvious (pp. 193-194, Isolation of the casein produced in E. coli cells; p. 198, R. Col.). Nagao teaches that the casein with the signal peptide produced in E. coli in its method was insoluble, and that the matured casein without the signal peptide is quite soluble (p. 199, L. Col. to R. Col.). The Examiner notes that Nagao uses the same signal peptide (Met-Lys-Leu-Leu-Ile-Leu-Thr-Cys-Leu-Val-Ala-Val-Ala-Leu-Ala-Arg-Pro-Lys) as that used in the instant Application (Specification, Table in pp. 40-41).
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Regarding the recitation of the wherein clauses (a) and (b) in Claims 21 ad 39, step ii) is not given patentable weight. Nagao clearly teaches the heating step, and therefore would necessarily obtain the expected result. "A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim." Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1172 (Fed._Cir. 1993). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). Note MPEP 2111.04. In this case, the wherein clause merely characterizes the results of those steps and does not distinguish the instantly claimed application from the application taught in the prior art. The same point applies to Claim 25.
Regarding Claims 21 and 39 step iii), Nagao teaches that the proteins in the cytoplasmic, periplasmic and inner membrane soluble fractions, and the fraction containing the cytoplasmic components and the solubilized inner membrane were separated by SDS-PAGE, and casein in the gels was detected with western blot, and then isolated by eluting electrophoretically (pp. 193-194).
Regarding Claim 23, Nagao teaches using lysozyme, which lyses the bacterial cell wall (p. 193, L. Col., bottom paragraph)
Regarding Claims 24, 27, and 38, Nagao teaches heating the suspension at 100 ˚C for 5 mins (pp. 193-194, Isolation of the casein produced in E. coli cells). One of ordinary skill in the art would find it obvious to adjust the time and temperature as a matter of experimentation and optimization to obtain high yield of solubilized casein. The adjustment of particular conventional working conditions is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results. Further regarding Claims 24 and 38, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05.
Regarding Claims 29-30, Nagao teaches construction of plasmids for expressing αs1-casein through isolation of αs1-casein (Figs. 1-5).
Regarding Claim 35, Nagao teaches E. coli bacteria (Abstract; Materials and Method).
Regarding Claim 36 and 40, Nagao teaches using buffers at pH 6.8 and 8 (p. 192, Expression of casein in maxicells; p. 193, Fractionation of cellular components).
Regarding Claim 39, Nagao has rendered all the features obvious supra.
Claims 26 and 37 are rejected under 35 U.S.C. 103(a) as being unpatentable over Nagao, as applied to Claims 21-25, 27, 29-32, 35-36, and 38-40, and in view of Ren et al. (Journal of Biotechnology 129 (2007) 668–673), hereinafter Ren, as evidenced by Goda et al. (Protein J (2010) 29:44–49).
The teachings of Nagao have been set forth supra. Nagao does not teach the feature of wherein the microorganisms are not lysed prior to heating in step (ii), and the heating in step (ii) lyses the microorganisms.
Nagao teaches that its recombinant casein are found in the insoluble fraction due to the hydrophobic signal peptide (Fig. 5; p. 199, R. and L. Cols.). Specifically, they form inclusion bodies as evidenced by Goda et al. (Abstract; Section 2.6).
Ren discloses the extraction of intracellular protein from E. coli using a novel thermolysis method which is highly effective in destroying the integrity of bacterial cell walls and releasing the recombinant protein, specifically an esterase (Abstract). Ren compared releasing the protein from E. coli at temperatures 60-90 ˚C, with 80 ˚C being the optimal temperature (Section 2.2; Fig. 1). Ren teaches that the thermolysis technique is cheap and can combine the cell disruption and protein purification, can kill E. coli cells eliminating possible release of recombinant host, and deactivates proteases which improves the product yield (p. 672, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to use heat treatment to lyse the cells replacing reagents such as the lysozyme in the method of Nagao because Ren has taught that thermolysis is not only highly effective in destroying the integrity of bacterial cell walls and releasing the recombinant protein, but is also a cost-effective way to disrupt cells, kill E. coli cells, and deactivates proteases which improves the product yield.
Claim 28 is rejected under 35 U.S.C. 103(a) as being unpatentable over Nagao, as applied to Claims 21-25, 27, 29-32, 35-36, and 38-40, in view of Geistlinger et al. (CA 3116718 A1; Of record) and Mohanty et al. (Saudi Journal of Biological Sciences (2016) 23, 577–583), hereinafter Mohanty.
Nagao does not teach wherein the microorganisms have been transformed with two or more nucleic acids, each encoding a different casein.
Geistlinger discloses compositions and methods for producing food products comprising recombinant components, wherein the recombinant component is a recombinant casein selected from the group consisting of β-casein, [Symbol font/0x67]-casein, [Symbol font/0x6B]-casein, α-S1-casein, and α-S2-casein (Abstract; Claims 1 and 75-76). The method comprises the steps of: a) obtaining a recombinant microbial host cell that is capable of producing a recombinant component; b) culturing the recombinant microbial host cell in a culture medium under conditions suitable for essentially eliminating or modulating an esterase activity and for production and/or secretion of the recombinant component to obtain a fermentation broth comprising the recombinant component and an essentially eliminated or modulated esterase activity; c) optionally purifying the recombinant component from the fermentation broth; and d) preparing a food product [0066]. In some embodiments, the milk protein component consists of one or more caseins [0207]-[0208].
Regarding Claim 28, Geistlinger teaches embodiments in which the recombinant polynucleotide comprises two or more expression cassettes [0169]. The recombinant protein that is typically encoded by the recombinant polynucleotide can be any recombinant e, g, recombinant β-lactoglobulin, recombinant α-lactalbumin, recombinant [Symbol font/0x6B]-casein, recombinant β-casein etc.
Mohanty provides the motivation to prepare different recombinant caseins, teaching their varying functions, e.g. peptides from bovine β-casein were responsible for phagocytizes in human, whereas peptides from [Symbol font/0x6B]-casein are used in immune therapy in HIV infection (Section 3.2); β-casein derived peptides are active against Enterococcus faecium, Bacillus megaterium (Table 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the method of Nagao and transform E. coli with different genes encoding different caseins. Applying a known technique to a known method ready for improvement to yield predictable results is the rationale supporting obviousness. See MPEP § 2143 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007). One would have been motivated to do so because Mohanty has taught that different caseins have different functions, for example in their actions against different pathogens.
Claim 33-34 is rejected under 35 U.S.C. 103(a) as being unpatentable over Nagao, as applied to Claims 21-25, 27, 29-32, 35-36, and 38-39, and in view of Broyard et al. (Dairy Sci. & Technol. (2015) 95:831–862; Of record), hereinafter Broyard.
Nagao does not expressly teach the soluble fraction recovered in step (iii) is acidified to a pH of about 4.
Broyard recognizes the use of casein in the food industry (Abstract). Broyard teaches the effect of different physicochemical conditions, including acidification, on casein molecules (Fig. 1). Broyard discloses that decrease in pH induces changes on intra- and intermolecular interactions of casein molecules, wherein the phosphoseryl residues and carboxyl groups change their ionization state (Section 2.1.5). During acidification, casein molecules are aggregated and their solubilities are minimal; At pH 4.6, the charge of caseins is equal to zero and precipitation or gelation is observed (Section 2.1.5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to combine the teachings of Broyard with that of Nagao, and acidify the soluble fraction of Geistlinger, starting at pH 4.6 and lowering as needed, to precipitate the casein if the artisan desires to isolate the soluble casein from the supernatant.
Response to Remarks:
The gist of Applicant’s argument is that that the recombinant casein is present in an insoluble fraction before heating, which is now stated in the amended claim, and that this feature is not disclosed by Geistlinger. Further, Geistlinger uses heat to preserve the recombinant component already in the soluble fraction and not recovery from insoluble fraction, and as such, does not teach the transfer and increase the amount of casein in the soluble fraction. Applicant also argues that the missing claim limitations are not inherent in Geistlinger because the process claimed begins with recombinant casein in an insoluble fraction.
The Examiner has considered the entire argument, which centers upon the casein being essentially found in the insoluble fraction. The arguments are moot because the new ground of rejection necessitated by the amendment does not rely on Geistlinger as primary art, but rather on Nagao. The Examiner notes that Nagao also teaches insoluble recombinant casein (p. 199, L. Col. to R. Col.).
Applicant argues that the Specification shows unpredictability, with the alpha-S2 casein was found essentially in the insoluble fraction, beta casein was largely or entirely in the insoluble fraction depending on the lysis protocol, and alpha-S1 casein was distributed between the soluble and insoluble fractions.
This argument is also not found persuasive because the new ground of rejection necessitated by the amendment does not rely on Geistlinger as primary art, but rather on Nagao, which teaches wherein at least part of the casein is present in the insoluble fraction of the composition. Vide supra.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 21-25, 27, 29-36, and 38-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-3, 12-16, 18, 20, and 23-24 of Application 19/503,556, hereinafter ‘556, in view of Nagao and Boyard.
Although the claims at issue are not identical, they are not patentably distinct from each other because they are drawn to the same subject matter and composition components.
Both the instant claims and ‘556 are drawn to a method providing a composition comprising microorganisms transformed with at least one nucleic acid encoding a casein, the microorganisms having been cultured under conditions that induce expression of the nucleic acid and production of the casein, wherein the microorganism composition has a pH of at least 6.5; heating the composition, and recovering the soluble fraction comprising casein.
The differences are cured by Nagao and Boyard, the teachings of which have been set forth in the 103 rejection supra.
Therefore, the claims are drawn to the same subject matter and are not patentably distinct from the instant claims.
Claims 21-25, 27, 29-36, and 38-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 40, 49-60 and 64 of Application 19/503,565, hereinafter ‘565, in view of Nagao and Broyard.
Although the claims at issue are not identical, they are not patentably distinct from each other because they are drawn to the same subject matter and composition components.
Both the instant claims and ‘565 are drawn to a method providing a composition comprising microorganisms transformed with at least one nucleic acid encoding a casein, the microorganisms having been cultured under conditions that induce expression of the nucleic acid and production of the casein, wherein the microorganism composition has a pH of at least 6.5; heating the composition, and recovering the soluble fraction comprising casein.
The differences are cured by Nagao and Broyard, the teachings of which have been set forth in the 103 rejection supra.
Therefore, the claims are drawn to the same subject matter and are not patentably distinct from the instant claims.
Response to Remarks:
Applicant argues that because the present Application has the earlier patent-term filing date than ‘556 and ‘565, the provisional obviousness-type double patenting rejections should be withdrawn upon allowance of the present case.
The Examiner will consider the request when the Application is found to be allowable.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Cai et al. (BMC Biotechnology (2020) 20:37) teaches one-step heating strategy for efficient solubilization of protein from inclusion bodies (Abstract). The art is relevant as the recombinant caseins also forms inclusion bodies.
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 JANICE Y SILVERMAN whose telephone number is (571)272-2038. The examiner can normally be reached on M-F, 10-6 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Erik Kashnikow can be reached on (571) 270-3475. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.Y.S./Examiner, Art Unit 1792
/ERIK KASHNIKOW/Supervisory Patent Examiner, Art Unit 1792
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