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 March 23, 2026 is acknowledged. Claims 4, 11, and 13-14 are canceled. Claims 1-3, 5-10 and 12 are pending and under examination.
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 1-3, 5-10 and 12 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, 5-7 and 12, 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 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 microarray 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). Friess discloses analysis of the human pancreas by reverse-phase high-performance liquid chromatography in conjunction
with mass spectrometry has revealed 15 to 30-fold variations among individuals with respect to GST A2 protein levels (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.
Response to Arguments
Applicant's arguments filed March 23, 2026 have been fully considered but they are not persuasive.
Regarding Response directed to the 103 rejection, Applicant argues Wezeman teaches the C4 column provides the best resolution for pancreatin mixtures, in contrast to the present invention using RP-UHPLC C18 column. Applicant argues the many differences between the two columns, and that it is not merely a simple substitution between the two. Applicant argues Martias fails to remedy the deficiency of Wezeman, 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 Wezeman and Martias. Applicant argues Friess teaches analysis of pancreatic enzymes CEL and kallikrein glandular that are not disclosed in Wezeman, but is directed to gene expression analysis in pancreatic disease using microarray technology, and does not teach the chromatographic separation techniques for these proteins.
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). Wezeman reference teaches RP-HPLC analytical methods 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, 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. Furthermore, it would be obvious to one of ordinary skill to try a different column size (i.e. C4 to C18) to optimize the separation method taught by Wezeman and Martias. Thus one of ordinary skill in the art would be motivated to optimize the RP-UHPLC method based on the teachings of Wezeman and Martias, to arrive at a further separated/purified enzyme profile of pharmaceutical API samples, with a reasonable expectation of success. Although Friess does not teach separation of CEL and kallikrein glandular with RP-UHPLC, Friess does teach identification of these two enzymes in pancreatic mixtures. Thus, it would have been obvious to one of ordinary skill in the art to employ the methods taught by Wezeman and Martias to separate these individual enzymes along with the enzymes taught in the aforementioned methods.
Conclusion
THIS ACTION IS MADE FINAL. 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 JESSICA EDWARDS whose telephone number is (571)270-0938. The examiner can normally be reached M-F 8am-5pm EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657
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