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
The instant application has a foreign application IN202221016286, filed March 23, 2022. Applicant’s amendment filed April 9, 2025 is acknowledged. Claim 11 is canceled and claims 12-14 are newly added. Claims 1-4 and 10 are amended. Currently claims 1-10 and 12-14 are pending and under examination.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 9, 2025 has been entered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 recites “the pancreatic protein mixture is partially purified” and claim 13 recites “the pancreatic protein mixture is substantially purified”. It is unclear the degree of ‘partially purified’ and the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The Specification defines ‘substantially’ referring ‘to a gradient that substantially elutes the mentioned pancreatic enzymes. The elution of mentioned pancreatic enzymes is about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, or 100%’. However, there is no clear definition of what constitutes ‘partially purified’ thus the Examiner interprets any purification less than 100% as ‘partially purified’.
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.
Claims 1-10 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Wezeman et al. (US 9,291,630, cited in IDS filed 7/29/2024, hereinafter “Wezeman”) in view of Friess et al. (Cell. Mol. Life Sci. 60 (2003) 1180–1199, cited in IDS filed 7/29/2024, hereinafter “Friess”) and Martias et al. (Molecules 2021, 26, 4111, pgs. 1-11, cited in PTO-892 mailed 10/09/2024, hereinafter “Martias”), as evidenced by Padfield et al. (Journal of Chroma. 1986, vol. 369, pgs. 133-141, cited in PTO-892 mailed 10/09/2024, hereinafter “Padfield”).
Regarding claims 1, 4-7 and 12-13, Wezeman teaches an improved process for the separation and analysis of one or more of pancreatic enzymes and variant thereof present in pancreatic protein mixture, a method for the separation, identification and quantification of multiple proteins in pancreatin active pharmaceutical ingredient (API) samples, wherein the sample analyzed is a pancreatin API powder, which reads on the pancreatic sample being a pharmaceutical composition that is a powder recited in claims 1 and 12 (abstract, col. 2, lines 12-14). Wezeman does not explicitly state the API sample is partially or substantially purified, however Wezeman teaches the API sample shows a purity of greater than 95%, thus necessarily meets the limitations of ‘partially purified’ recited in claim 4 and ‘substantially purified’ in claim 13 (col. 9, lines 20-21).
Wezeman teaches the method comprises a) preparing the soluble protein mixture from pancreatic sample (Pancreatin API samples are prepared as described below in Example 1), and the soluble fraction of pancreatin API after centrifugation is used for RP-HPLC analysis (col. 5, lines 15-17). Wezeman teaches the API can optionally be treated with a reducing agent in the sample loading buffer, which cleaves disulfide bonds covalently linking other protein subunits (col. 6, lines 8-11 ). Wezeman teaches to optimize separation of pancreatin proteins on RP-HPLC, different columns, C4, C8, and C18, and various elution gradients were tested, and the best resolution was obtained from a C4 column using elution conditions described in Table 1 (col. 5, lines 25-30). Wezeman teaches suitable separating solution in mobile phase comprises mobile Phase A and mobile phase B and are separated by running a linear-segmented gradient of acetonitrile containing 0.1% trifluoroacetic acid (TFA), wherein solvent A is 0.1% TFA in water and solvent B is 0.1% TFA in acetonitrile, wherein the mobile phase is performed in more than one gradient, which meets the limitations of claims 1 and 5-6 (col. 5, Table 1). Wezeman teaches the separated pancreatic proteins and variant thereof are further analyzed by one or more suitable techniques selected from CE-SDS, SOS-PAGE, MALDI-TOF-MS, MS, SE-HPLC profile and RP-HPLC, and electrophoretic separations by SDS-PAGE are performed on peaks collected from RP-HPLC to determine the MW of the proteins, which meets the limitation of claim 7 (col. 6, lines 2-4).
Wezeman does not explicitly teach a ultra-high-performance liquid chromatography is used for the separation of the API. However, Martias teaches optimization of metabolomics of urine, feces, blood, and saliva using reverse phase UHPLC (title, pg. 11, sec. 3.2.1). The chromatography system was equipped with a reverse-phase C18 column and a mobile phase A and B solvent system (pg. 11, sec. 3.2.1). The mobile phase A (ultrapure water) and mobile phase B (methanol) with an organic solvent (formic acid) (pg. 11, sec. 3.2.1). The run was conducted at a constant flow rate of 0.4mL/min for 24 min using a multi-step gradient (pg. 11, sec. 3.2.1). Martias teaches the chromatography system as being performed in more than one gradient (pg. 11, sec. 3.2.1).
Wezeman teaches elution of the proteolytic digested products, Trypsin, chymotrypsin, elastase (three types: elastase, elastase-I and elastase-II), carboxypeptidase (two types: carboxypeptidase-A and carboxypeptidase-B), phospholipase A lipase, colipase, and amylase are identified in a pancreatin API sample, which meets these limitations listed in claim 1 (col. 9, lines 51-55). Wezeman does not explicitly teach carboxyl ester lipase (CEL lipase) or Kallikrien glandular.
However, Friess teaches analysis of the human pancreas by reverse-phase high-performance liquid chromatography and teaches carboxyl ester lipase (CEL lipase) and Kallikrien glandular (comprised mainly pancreatic enzymes), which are produced by acinar cells, such as kallikrein 1, protein disulfide isomerase (PDI), chymotrypsin-like
proteinase, and carboxyl ester lipase (pg. 1194, col. 1, para 2; pg. 1195, col. 1, para 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of separating pancreatic proteins/enzymes from a pharmaceutical composition taught by Wezeman with the RP-UHPLC C18 column taught by Martias with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to try other separation/purification methods and columns to effectively separate the pancreatic protein mixture, as disclosed by Wezeman. Further, it would have been prima facie obvious to separate the enzymes taught by Wezeman (Trypsin, chymotrypsin, elastase (three types: elastase, elastase-I and elastase-II), carboxypeptidase (two types: carboxypeptidase-A and carboxypeptidase-B), phospholipase A lipase, colipase, and amylase), as well as separate the pancreatic enzymes taught by Friess (CEL lipase and Kallikrien glandular) with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to separate and distinguish these individual enzymes in a pharmaceutical composition to measure molecular weights of each enzyme in the composition as taught by Wezeman.
Regarding claims 2-3 and 8-10, Wezeman teaches PLA2 co-eluted with RP-HPLC peaks 1&2, trypsin co-eluted with peaks 4-7, elastase co-eluted with peak 15, and amylase co-eluted with peak 19 (claim 9). Wezeman discloses in Table 1 (col. 5), when solvent B was increased to 40-50% between 28-37 minutes, PLA2, trypsin, the lipases, elastases, and chymotrypsin were detected as shown in in Fig. 14 (pg. 16). Carboxypeptidase A & B were eluted substantially between 36-45 minutes, which solvent B increased from 50-90% (Fig. 14, pg. 16; Table 1, col. 5). Wezeman discloses the retention time of each peak in Fig. 5 (pg. 6). Wezeman teaches the flow rate was maintained between 1-1.2 mL/min (Table 1, col. 5). Wezeman does not disclose the specific concentrations, time frames, and flow rates recited in claims 2-3 and 8-10. However, the selection of specific concentrations, flow rates, and time frames clearly would have been a routine matter of optimization for the specific chromatography utilized, using standard laboratory techniques available at the time of filing on the part of the artisan of ordinary skill, said artisan recognizing that the effectiveness of the method of eluting fractions would have been affected by the concentration, flow rate, and time frame of the gradient tailored to the specific chromatography. As evidenced by Padfield, chromatograms vary between columns that are eluted with the same sample at different flow rates and elution time gradients, however the overall elution profile is similar even though the elution times are altered (pg. 139, para 2). See MPEP 2144.05
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of separating pancreatic proteins/enzymes from a pharmaceutical composition taught by Wezeman by routine optimization and standard laboratory practices when utilizing the RP-UHPLC C18 column taught by Martias to separate the pancreatic enzymes taught by Wezeman and Friess with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to employ the solvent scheme of eluting the specific pancreatic enzymes at specific solvent concentrations based on the prior art and optimize the method based on the specific flow rate and time frame using the RP-UHPLC C18 column to successfully elute all the recited enzymes in the claimed method.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Wezeman, Martias, and Friess as applied to claims 1-10 and 12-13 above, and further in view of Potthoff et al. (CA 2528906 C, hereinafter “Potthoff”).
Wezeman teaches the pharmaceutical API’s are derived from porcine pancreas, and does not explicitly teach the pancreatic protein mixture is microbially synthesized.
However, Potthoff teaches novel methods to analyze and identify proteins in mixtures of digestive enzymes in the context of medicinal products comprising said enzyme mixtures, wherein the enzymes mixtures are microbially synthesized lipases, proteases, and amylases (abstract, pg. 4, para 3).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of separating pancreatic proteins/enzymes from a pharmaceutical composition taught by Wezeman with the RP-UHPLC C18 column taught by Martias, and analyze a microbially synthesized API pancreatic protein mixture as taught by Potthoff with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to analyze all types of pancreatic API protein mixtures using the modified method taught by Wezeman and Martias, wherein the pancreatic API protein mixtures are synthesized by human, porcine, or microorganisms.
Response to Arguments
Applicant's arguments filed April 9, 2025 have been fully considered but they are not persuasive.
Regarding Response directed to the 103 rejection, Applicant argues Goke fails to teach separating and analyzing with a RP-UHPLC C18 column, all of the claimed pancreatic enzymes. Applicant argues the RP-HPLC separation Goke teaches only separates a few enzymes, and acknowledges variations in the quality of the enzyme profile. Applicant argues Martias fails to remedy the deficiency of Goke, and teaches UHPLC(RP)-MS in the context of generating a metabolic map from urine, blood, saliva, and feces, which are very different in nature than the presently claimed pancreatic protein mixture, thus one of ordinary skill in the art would not have been motivated to combine the methods taught by Goke and Martias.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See 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). Furthermore, the newly applied Wezeman reference teaches RP-HPLC analytical methods combining Wezeman and Goke’s elution schemes to successfully elute 10 out of the 12 enzymes. It would be obvious to one of ordinary skill in the art to utilize a more highly specialized method for separating proteins, such as RP-UHPLC as taught by Martias, to further separate/identify other pancreatic enzymes in pancreatic API samples. Although Martias does teach RP-UHPLC methods for creating metabolomic profiles based on different sample sources (urine, etc.), the fact that Martias successfully purifies and separates protein mixtures from such crude samples, underlines the success of the RP-UHPLC method. Thus one of ordinary skill in the art would be motivated to optimize the RP-UHPLC method based on the teachings of Wezeman, Goke, and Martias, to arrive at a further separated/purified enzyme profile of pharmaceutical API samples, with a reasonable expectation of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA EDWARDS whose telephone number is (571)270-0938. The examiner can normally be reached M-F 8am-5pm EST.
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/JESSICA EDWARDS/
Examiner
Art Unit 1657
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
Prosecution Insights