The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 14 and 18 are rejected under 35 U.S.C. 112(b) as being indefinite in that they fail to point out what is included or excluded by the claim language. These claims are omnibus type claims.
Claims 2, 5-8 and 15 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 (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Is claim 2 only directed to method (b) or is it directed to both methods (a) and (b)? With respect to claim 5, it is not clear if applicant is considering the reference to “a mobile phase in a combined FMA-HPLC method” as limiting the solution containing the fluorescent dye to a particular mobile phase in one of the references cited in the instant disclosure (e.g. reference 3 or reference 9, see page 12, lines 10-19 of the originally filed specification) or if there are multiple mobile phases that are used for a “combined FMA-HPLC method”? The language cancelled from claim 5 in the amendment filed 3/26/2024 was substantially clearer than the language that remains as instant claim 5. With respect to claim 6, it is not clear if the language “for the quantification of polysorbate in an aqueous formulation containing polysorbate and one or more (poly)peptides” found in claim 1 already limits claim 1 to polysorbate that intended for pharmaceutical use, the specifically claimed polysorbate products and/or polysorbate products suitable for parenteral administration. For examination purposes, if the aqueous formulation containing polysorbate and one or more (poly)peptides is a drug or parenteral formulation containing polysorbate 20 or polysorbate 80, the limitation will be considered as being met. With respect to claim 7, it is not clear what differentiates non-binding, low-binding and medium-binding surfaces. This issue concerns the relative level of binding that distinguishes between the surfaces as well as what substance is binding to the surfaces. For example, is the binding classification in reference to binding the dye, the (poly)peptide, the polysorbate or something else? For examination purposes, plastic cuvettes and/or multiwell plates/microplates will be treated as meeting the claim limitation. With respect to claim 15, it is not clear what distinguishes use of the method of claim 1 from the method of claim 1. For examination purposes, examiner will treat claims 1 and 15 as equivalent.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2, 16 and 19 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The language “for the quantification of polysorbate in an aqueous formulation containing polysorbate and one or more (poly)peptides” found in claim 1 so that claims 2, 16 and 19 fail to further limit claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1-2 14-16 and 18-19 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Hong (Authorea 16 November 2020). In the last paragraph before the conclusion section on page 8 of the paper Hong teaches that For long-term storage of mAbs formulated with polysorbate (PS), difficult to remove lipases that were identified need to be further cleared during the downstream purification. In order to evaluate the mAb1 product stability, PS was analyzed using two different methods after 4 weeks of storage at 25 °C. Fluorescence micelle assay (FMA) was utilized for PS quantification and 4-methylumbelliferyl decanoate (4-Mud) assay for lipase activity. Table 2 summarized the PS quantification, lipase activity and its relative abundance in different processes samples. In harvest cell culture fluid (HCCF), PS degraded from 400 ppm at day 0 to approximately 20 ppm after 4 weeks of incubation. This result was expected due to the high host cell protein (HCP) concentration in the cell culture fluid. After ProA purification, PS content was measured to above 200 ppm for both perfusion processes but less than 100 ppm for the fed-batch process. Lipase activity also shows great differences between perfusion and fed-batch processes after the ProA purification. On page 4 the publication, Hong teaches the fluorescence micelle assay (FMA) that was used to determine the concentration of polysorbate (PS) in the mAb1 samples. The FMA reagent contains 0.15 M sodium chloride, 0.05 M Tris, 5% ACN, 5 mM N-phenyl-1-naphthylamine and 15 ppm (parts per million) Brij35 with a pH 8.0. 10 ml of sample was mixed with 240 ml of FMA reagent in a 96 well plate (Greiner Bio-One, Monroe, USA) and shaken for 60 sec at 35 °C. The fluorescence detector, Tecan Spark was set to an excitation wavelength of 350 nm and an emission wavelength of 420 nm. For quantitation, a calibration curve ranging from 0.1 mg/ml to 0.6 mg/ml PS was used as standard.
With respect to claim 1, the above description anticipates the claim because the FMA samples are looking at formulations of mAb1 to determine polysorbate degradation from host cell protein, the FMA is a method for the quantification of polysorbate in an aqueous formulation containing polysorbate and one or more (poly)peptides; wherein the method has the following steps: providing a sample of the aqueous formulation; adding of a solution containing the fluorescent dye N-phenyl-1-naphthylamine to the sample to obtain a fluorescent dye containing sample to be tested in a fluorescence micelle assay; incubating the fluorescent dye containing sample of step (the shaking step at 35 °C); performing a fluorescence micelle assay with the fluorescent dye containing sample obtained in step and; determining the content of polysorbate present in the sample from the fluorescence micelle assay performed in step (see the table of results); with the proviso that the method (a) and the method (b) is each performed without the use of a HPLC-system (no HPLC was used). Claims 2, 14-16 and 18-19 are also anticipated based on either their designation as an omnibus claim or as a claim that is equivalent to claim 1 as explained in the rejections under 35 U.S.C. 112(b) or 35 U.S.C. 112(d) above.
With respect to claim 3, the shaking step at 35 °C and the use of the Tecan Spark fluorescence detector anticipates at least all of the conditions related to step (a.3) and the use of a fluorescence detector. With respect to claim 4, mixing of the sample with the FMA reagent anticipates the claim. With respect to claim 5 and 17, the FMA reagent of Hong is the same as the reagent taught on page 12, lines 10-19 of the originally filed specification so that the claims are anticipated. With respect to claims 6 and 12, the fact that the mAb1 is intended for drug substances (see at least the paragraph bridging pages 2-3) and the last full paragraph on page 7 discusses PS20 degradation, the limitation of claims 6 and 12 are anticipated. With respect to claims 7-8, the 96 well plate anticipates these claims. With respect to claim 9, the use of the Tecan Spark fluorescence detector anticipates automation of at least one of the steps. With respect to claim 10, the mAb1 antibody anticipates the claim limitation. With respect to claim 13, the fact that the FMA was looking at polysorbate degradation in mAb1 formulations anticipates the method being carried out during the development, manufacture, shelf life, or storage time of the aqueous formulation, whereby the aqueous formulation contains polysorbate and one or more (poly)peptides.
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.
Claim 11 is rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Hong as described above. Hong does not teach the mAb1 antibody as a therapeutic (poly)peptide(s), which are used for the prevention or treatment of a disease or a disorder. However, page 31, lines 8-15 of the originally filed specification teaches that in the experiments presented in the specification, five different mAbs were used, with different physicochemical characteristics, and the standard protein alpha-lactalbumin was used for investigating the specificity of the FMA. The detailed characteristics of these proteins are listed in Table 1 with mAb1 as one of the five. Thus either mAb1 of Hong anticipates the limitation of claim 11 or it shows the obviousness of preforming the Hong method on formulation containing polysorbate and therapeutic (poly)peptide(s), which are used for the prevention or treatment of a disease or a disorder because of the possible presence of host cell proteins capable of degrading the polysorbate in the formulation as taught by Hong.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The additionally cited art is related to determining polysorbate in various biologic formulations. Of particular relevance are the Wenger (Analytical Biochemistry 2005), Zheng (Pharmaceutical Development and Technology 2015), Arora (Journal of Pharmaceutical Innovation 2015), Scholz (Journal of Fluorescence 2018) and Parmar (Indian Drugs 2019) teaching at least partially automated methods for determining polysorbate in biologic/drug/pharmaceutical formulations using a fluorescent dye that incorporates into the polysorbate micelles such that replacement of their respective dyes with the claimed N-phenyl-1-naphthylamine would show the obviousness of one or more of the instant claims. Examiner also notes that the Scholz reference teaches a shaking step prior to the measurement (see the paragraph bridging pages 466-467).
Examiner has ordered a copy of another reference (XIN, Zhong-shuai et al, “Fluorescence photometry determination of polysorbate 20 in recombinant human growth hormone injection” Chinese Journal of Pharmaceutical Analysis 2007, 27(12), 1887-1890) that appears be relevant to the instant invention because it appears to teach a method similar to that taught in the applied Hong reference. This reference was not available at the time this action needed to be submitted, but will be evaluated against whatever claims are submitted in response to this office action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Arlen Soderquist whose telephone number is (571)272-1265. The examiner can normally be reached 1st week Monday-Thursday, 2nd week Monday-Friday.
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/ARLEN SODERQUIST/Primary Examiner, Art Unit 1797
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