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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-8) in the reply filed on 05/05/2026 is acknowledged.
Claims 9-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-8 are directed to the elected invention and have been examined on their merits.
Priority
The present application is a 371 National Stage Entry of PCT/EP2021/074522 (filed on 09/06/2021) and claims priority to foreign applications EP20211184.5 (filed on 12/02/2020) and EP20194935.1 (filed on 09/07/2020).
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings are objected to for the following reasons.
Rule 1.84(u)(1) requires that “[v]iew numbers must be preceded by the abbreviation “FIG.”. Accordingly, the labels should be amended to “FIG. 1”, “FIG. 2”, etc.
Rule 1.84(u)(1) also requires that “[p]atrial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. Accordingly, FIG. 7 should be amended to show FIG. 7A and FIG. 7B, FIG. 10 should be amended to show FIG. 10A, 10B, and 10C (rather than FIG. 10 and FIG. 10 (cont.)), and FIG. 11 should be amended to show FIG. 11A and 11B.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 2 is objected to because the word “min” is an abbreviation and should therefore be punctuated with a period. Nonetheless, because the claim also uses the unit “hours” (rather than hrs), it is recommended that the word simply be amended to read “minutes”.
Claim 7 is objected to because element (c) has the phrase “in the reaction mixture” duplicated.
Appropriate correction is required.
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.
Claim 1-8 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 1 is indefinite because it limits the 4-MU ester to “a saturated unbranched-chain fatty acid (C6-C16)”. The use of a parenthetical renders the claim indefinite because it is unclear if the fatty acid must be 6-16 carbons or if this is merely an exemplary fatty acid length.
In the interest of compact prosecution, it is recommended that applicant remove the parenthetical and insert a further limitation that the 4-MU ester “is a saturated unbranched-chain fatty acid” and the 4-MU ester is 6-16 carbons in length. For the purposes of applying prior art, the claim has been interpreted under this interpretation.
Claims 2-8 are also indefinite because they inherit this language without clarifying the intended length of the fatty acid chain.
Claims 1-2 are further considered to be indefinite because they refer “the sample” in step (c) of claim 1 and line 1 of claim 2. Step (b) introduces “at least one sample”. Accordingly, it is unclear if the incubation step occurs with a single sample (i.e., the sample) or more than one sample.
In the interest of compact prosecution, step (c) is interpreted to require incubating “the at least one sample” and it is recommended that applicant amend the claim to instead read “the at least one sample”.
Claim 1 is further considered to be indefinite because it refers to “the released chromophore 4-MU” twice in step (d) but there is no antecedent basis for this limitation.
In the interest of compact prosecution, this phrase has been interpreted to refer to detecting “a released chromophore 4-MU” and it is recommended that applicant amend the claim to instead read “a released chromophore 4-MU”.
Claim 4 is indefinite because it recites “the surfactant…is not polyethylene glycol tert-octylphenyl ether (Triton X-100) and not polyethylene glycol nonylphenyl ether (NP-40)”. Because of the use of parentheticals, it is unclear if the claim excludes all PEG tert-octylphenyl ethers and nonylphenyl ethers or only Triton X-100 and NP-40.
In the interest of compact prosecution, the claims have been examined as excluding all tert-octylphenyl ethers and nonylphenyl ethers.
Claim 4 is further rejected because it recites trademarks or trade names. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b). See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademarks Zwittergent™ and Triton™ X-100 and the trade name “NP-40” are used to identify/describe particular surfactants and, accordingly, the identifications/descriptions are indefinite. If applicant wishes to limit the surfactant to the surfactant known by these trademarks or trade name, the trademarks and trade names should be replaced with generic terminology (e.g., replacing “Triton X-100” with t-Octylphenoxypolyethoxyethanol, Polyethylene glycol tert-octylphenyl ether).
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 (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 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 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Jahn et al. (Pharmaceutical Research, 2020, Vol. 37(118), pages 1-13; cited in IDS filed on 06/24/2024) in view of Yoo et al. (Cell Chemical Biology, 2020, Vol. 27, pages 143-157; cited in IDS filed on 03/06/2023) and Prim et al. (Journal of Molecular Catalysis, 2003, Vol. 22, pages 339-346).
Jahn teaches that polysorbates are critical stabilizers in biopharmaceutical protein formulations but they may degrade in drug substances or drug produce Sets during storage (abstract). Particularly, degradation by lipases present in host cell proteins is a suspected root cause (Id.). Accordingly, Jahn describes an assay to detect lipolytic activity in biopharmaceutical drug substances and drug product formulations (Id.).
Regarding claim 1, Jahn teaches a method for detecting lipase activity in a sample comprising a recombinant protein for the reasons discussed below.
With respect to step (a), Jahn teaches providing samples (i.e., at least one sample) consisting of 20 mM L-histidine at pH 6, 250 mM sucrose, 0.02% PS80, 10 mg/mL mAb1 (i.e., a recombinant protein produced in a eukaryotic cell; see, p. 3, left col., par. 1 which discusses the use of ‘a proprietary CHO cell line expressing a non-therapeutic monoclonal antibody’), and 0.5% cell culture harvest fluid (containing a mixture of lipases), or 0.025 mg/mL PPL (porcine pancreatic lipase)(p. 3, right col., par. 3). As such, Jahn teaches a step of providing at least one sample comprising a recombinant protein produced in a eukaryotic cell.
With respect to step (b), Jahn teaches that the assay involves the combination (i.e., contacting) of the sample, HCMB (high concentration matrix buffer), and organic solvent (p. 3, left col., par. 2). The HCMB in the protein containing solution assay consisted of 208 mM BIS-TRIS at pH 6 (i.e., a buffer having a pH of about 4 to about 9). Jahn further teaches that the composition comprises 100 µM 4MuO (p. 3, right col., par. 3)(i.e., a substrate comprising the chromophore 4-methylumbelliferyl in the form of a 4-MU ester). Jahn’s assay formulation also comprises 600 mM NaCl and 5.2 mM CaCl2 (i.e., a non-buffering salt; see [101] of the specification for support of this interpretation)(p. 3, right col., par. 3).
Accordingly, Jahn teaches a reaction solution comprising a buffer, a surfactant (PS80), a substrate comprising the chromophore 4-methylumelliferyl (4-MU), and a non-buffering salt. And although Jahn’s protein assay uses PS80 as a surfactant (p. 3, right col., par. 3), Jahn teaches that polysorbates are added to biopharmaceutical protein formulations in order to minimize interfacial stress and these polysorbates (particularly PS20 and PS80) are prone to degradation from residual catalytic activity of lipases (p. 2, left col., par. 1-4). Jahn also tested the surfactant poloxamer and found that the surfactants had “a noticeable impact on lipolytic activity”, likely due to the fact that polysorbates drastically decreased 4MU formation because they are competitive substrates/inhibitors for the lipases, because the 4MuO was incorporated into the micellar structure of polysorbate thereby reducing its concentration in aqueous medium, or because the lipase enzymes were structurally affected by the polysorbates (p. 8, right col., par. 2). Comparatively, poloxamer positively influenced the lipolytic activity of CCHF (p. 9, left col., par. 1). Accordingly, Jahn provides ample suggestion to use poloxamer as a surfactant in the 4-MU assay instead of polysorbates because of the deleterious effects on 4-MU generation. Poloxamer is a non-denaturing surfactant not having an ester-bond, wherein the surfactant is a non-ionic or zwitter-ionic surfactant (this position is supported by [057] of applicant’s disclosure).
With respect to step (c), Jahn teaches a step of incubating the sample and the substrate in the reaction mixture by teaching that the assay is incubated and read for between 24 hours to 300 hours (p. 4, left col., par. 3).
With respect to step (d), Jahn teaches observing fluorescence measurements for reading concentration of 4Mu (Id.). Jahn also teaches that 4-methylumbelliferyl oleate was used because the hydrolysis reaction product (4Mu) can be detected by fluorescence emission (p. 4, right col., par. 3; Fig. 1). Accordingly, Jahn teaches detecting lipase activity by measuring hydrolysis of 4MuO and detecting the fluorescence intensity of the released chromophore 4-MU over time, while incubating the sample and the substrate in the reaction mixture according to step (c).
Thus, Jahn differs from the instant claims in that it does not teach or suggest that the reaction mixture comprises a substrate comprising the chromophore 4-methylumbelliferyl (4-MU) in the form of a 4-MU ester, wherein the 4-MU ester is a saturated unbranched-chain fatty acid (C6-C16) 4-MU ester.
Nonetheless, Yoo et al. investigates the inhibition of rPfMAGLLP (recombinantly expressed monoacylglycerol lipase-like protein in P. falciparum). As part of the method to determine structural and functional relationship to human MAGL, Yoo investigates PfMAGLLP’s ability to process various fluorogenic lipid ester substrates with different chain lengths (p. 147, right col., par. 2). Namely, Yoo tested 4-MU acetate, 4-MU butyrate, 4-MU octanoate, 4-MU decanoate, and 4-MU monosaturated oleate (p. 147, right col., par. 2 and Fig. 3C).
Prim et al. similarly discusses the use of 4-MU substrates for detecting lipase activity. Specifically, Prim teaches that the use of lipidic substrates linked to fluorescent compounds provides a sensitive method for detection and quantification of enzyme activity in biological systems (p. 340, left col., par. 2). Among the fluorogenic substrates, 4-methylumbelliferone-derivatives, commercially available in a wide range of chain-length, have shown to be useful tools for lipase activity determination (p. 340, left col., par. 2). Finally, Prim teaches that detection and determination of lipase activity using MUF-derivative substrates provides a fast, sensitive and accurate system to gain information about the biochemical and molecular properties of lipases, allowing rapid and valuable decisions about the potential biotechnological applications of the lipases studied (p. 346, left col., par. 1).
Accordingly, because Yoo demonstrates the conventional use of various substrates comprising the chromophore 4-methylumbelliferyl in the form of a 4-MU ester in assays for determining lipase activity and because Prim teaches that it is routine and advantageous to use various MUF-derivative compounds for detecting lipase activity, it would have been obvious to have used a 4-MU ester which is a saturated unbranched-chain fatty acid (C6-C16) 4-MU ester by simply substituting Jahn’s 4-MU ester with an ester having these properties. The substituted components and their functions were known in the art as demonstrated by Yoo’s disclosure of the use of such components in detecting lipase activity. And although the substrates having C6-C16 may exhibit varying or advantageous reaction efficiency, Yoo demonstrates that lipases such as MAGL are “capable of hydrolyzing a variety of monoglycerides into free fatty acids and glycerol” and can “process various fluorogenic lipid ester substrates bearing different chain lengths” (p. 147, right col., par. 2). As such, there would have been a reasonable expectation that Jahn’s method for detecting lipase activity would function with a 4-MU ester having the recited characteristics. This obviousness is based upon the “Simple Substitution of One Known Element for Another to Obtain Predictable Results” rationale set forth in in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007).
Accordingly, Jahn in view of Yoo and Prim renders obvious claim 1.
Regarding claim 2, as discussed above, Jahn teaches an incubation period of ~24 hours to ~300 hours (p. 4, left col., par. 3). However, Jahn also teaches observations over shorter incubation periods. When assessing the effect of an inhibitor of lipase, Jahn performed the assay after 1 hour of incubation (a time falling within the claimed range). Additionally, a person having ordinary skill in the art would have been motivated to perform the assay over a shorter period of time such as between 2 minutes and less than 5 hours in order to more rapidly detect lipase activity in a sample. For example, Prim teaches the assessment of lipase activity over a time period of 15 minutes (p. 341, left col., par. 3; p. 342, left col., par. 1). As discussed above, Prim teaches that detection and determination of lipase activity using MUF-derivative substrates provides a fast, sensitive and accurate system to gain information about the biochemical and molecular properties of lipases, allowing rapid and valuable decisions about the potential biotechnological applications of the lipases studied (p. 346, left col., par. 1). Thus, it would have been obvious to have modified Jahn’s methods such that they involve incubation for a shorter time period (such as 15 minutes, as demonstrated by Prim or 1 hour, as shown in Jahn) because such time periods allow for fast, sensitive and accurate analysis of lipase activity (rather than by assessing long term shelf storage over hundreds of hours). This obviousness is based upon the “Some Teaching, Suggestion, or Motivation in the Prior Art That Would Have Led One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior Art Reference Teachings To Arrive at the Claimed Invention” rationale set forth in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007). See MPEP 2143(I)(G).
Regarding claim 3, as discussed above, Jahn in view of Yoo and Prim renders obvious the use of 4-MU derivatives including 4-MU octanoate and 4-MU decanoate.
Regarding claim 4, as discussed above, Jahn in view of Yoo and Prim renders obvious the use of a surfactant such as poloxamer. Poloxamer satisfies the claim because it meets element (b)(iii).
Regarding claim 5, as discussed above, Jahn in view of Yoo and Prim renders obvious the use of buffer BIS-TRIS.
Regarding claim 6, as discussed above, Jahn in view of Yoo and Prim renders obvious the use of BIS-TRIS at pH 6. Accordingly, Jahn in view of Yoo and Prim renders obvious the use of a buffer which has a pH of about 5 to about 7.5.
Regarding claim 7, as discussed above, Jahn in view of Yoo and Prim renders obvious the use of NaCl and CaCl2. Specifically, Jahn teaches 600 mM NaCl and 5.2 mM CaCl2. Accordingly, the method comprises a non-buffering salt and the non-buffering salt is NaCl or CaCl2 (note that the claim is open to multiple salts based on the comprising language).
Regarding claim 8, as discussed above, Jahn in view of Yoo and Prim renders obvious the method wherein the sample is a cell culture harvest fluid (considered to be equivalent to “harvested cell culture fluid”) and also teaches the use of such methods in drug substances and drug products (p. 2, right col., par. 1). Additionally, Jahn’s “recombinant protein” is a non-therapeutic monoclonal antibody which is not a lipase and/or an enzyme having lipase activity and the recombinant protein is selected from a group consisting of an antibody.
Conclusion
No claim is allowed.
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/GRANT C CURRENS/Examiner, Art Unit 1651
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