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 .
Priority
Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional applications 63/315,897 (filed on 03/02/2022), 63/411,899 (filed 09/30/2022), 63/417,873 (filed 10/20/2022), 63/436,854 (filed 01/03/2023), and 63/448, 655 (filed 02/27/2023).
Election/Restrictions
Applicant’s election without traverse of Group I, corresponding to claims 1-11, 25-29, and 30-43, in the reply filed 06 April 2026 is acknowledged. Claims 14-24 and 44-47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06 April 2026. Claims 12 and 13 were cancelled in the reply filed on 06 April 2026.
Specification
The specification is objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)).
Drawings
The drawings are objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)).
The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation “FIG.” Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation “FIG.” must not appear.
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.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: Figure 1: C23, C93, C139, C199, C219, C22, C96, C152, C208, VL, CL, CH1, VH, C231, C234, CH2, CH3, C266, N302, C326, C372, and C430. Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. 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.
The drawings are objected to because: (a) Figure 5 does not include units for the second panel x-axis above the 15 insulin concentration (O, 5, 10, 15); (b) there are no units associated with Figure 19, x-axis, "Time Point"; (c) there are no units associated with Figure 22, x-axis, "Time Point"; (d) there are no units associated with Figure 24a-c, x-axis, "Time Point"; (e) there are no units associated with Figure 25a-c, x-axis, "Time Point; (f) there are no units associated with Figure 26a-b, x-axis, "Time Point"; (g) there are no units associated with Figure 46, x-axis, "Time"; (h) there are no units associated with Figure 47, x-axis, "Time" (i) there are no units associated with Figure 48, x-axis, "Time"; (j) there are no units associated with Figure 49, x-axis, "Time"; (k) there are no units associated with Figure 50, x-axis, "Time"; (I) there are no units associated with Figure 51, x-axis, "Time"; (m) there are no units associated with Figure 52, X- axis, "Time"; (n) there are no units associated with Figure 53, x-axis, "Time"; (o) there are no units associated with Figure 54, x-axis, "Time"; (p) there are no units associated with Figure 55, x-axis, "Time"; (q) there are no units associated with Figure 56, x-axis, "Time"; (r) there are no units associated with Figure 57, x-axis, "Time". 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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (paragraphs 0150 and 0278). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term Millistak+TM (paragraph 0344), MabSelect™ (paragraph 0349), ProSepTM (paragraph 0349), MabCaptureTM (paragraph 0349), PorosTM (paragraph 0381), CaptoTM (paragraph 0381), CaptoTM (paragraph 0399), PorosTM (paragraph 0399), Bio-Gel™ (paragraph 0433), CaptoTM (paragraph 0638), MabSelectTM (p. 216, enumerated example 270), MabCaptureTM p. 216, enumerated example 270), MabSelect™ (p. 218, enumerated example 287), MabCaptureTM (p. 218, enumerated example 287), CaptoTM (p. 218, enumerated example 288), PorosTM (p. 218, enumerated example 289), CaptoTM (p. 218, enumerated example 291), Fractogel™ (p. 218, enumerated example 291), CaptoTM (p. 218, enumerated example 292), Fractogel™ (p. 219, enumerated example 293), CaptoTM (p. 219, enumerated example 297), Fractogel™ (p. 219, enumerated example 297), MabSelectᵀ (p. 223, enumerated example 327), CaptoTM (p. 224, enumerated example 328), FractogelTM (p. 224, enumerated example 328), SartobindTM (p. 224, enumerated example 328), CaptoTM (p. 224, enumerated example 329), MabSelectTM (p. 227, enumerated example 353), CaptoTM (p. 229, enumerated example 378), MabSelectTM (p. 233, enumerated example 395), CaptoTM (p. 233, enumerated example 398) which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as TM, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1 and 30 are objected to because of the following informalities: “the pH to from about 5” should read “the pH to about 5”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-11 and 25-42 are 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.
The term “about” in claims 1, 3, 6-7, 27-28, 30, 32, , and 35-36, is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, 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 pH and concentration of acetate are rendered indefinite by use of the term “about”. The dependent claims do not add additional clarity and, therefore, are also indefinite.
Claims 3 and 32 recite the limitation “transient pH”. It is unclear what transient is in reference to, i.e. how long is transient and from pH is this transient pH adjusted from and subsequently back to. For the purposes of compact prosecution and applying prior art, “transient pH” will be interpreted to be any time frame of pH adjustment, where the pH is adjusted to this target (about 4-5.5) and then readjusted to anything outside this target (about 4-5.5). The dependent claims do not add additional clarity and, therefore, are also indefinite.
Claims 9, 29, and 38 contains the trademark/trade names MabSelectTM, rProtein A SepharoseTM, ProSepTM, MabCaptureTM, AmsphereTM, PelliconTM, KvickTM, CentramateTM, and CentrasetteTM. 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) or 35 U.S.C. 112 (pre-AIA ), second paragraph. 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 trademark/trade name is used to identify/describe Protein A resins and membrane filters and, accordingly, the identification/description is indefinite.
Regarding claims 25 and 30, the phrase “an anti-IL4Rα” renders the claim indefinite because it is unclear whether the limitation is part of the claimed invention. Anti-IL4Rα appears to be a specific example of an antibody in this claim, whereas all of the other steps are drawn to generic antibodies. See MPEP §2173.05(d). The dependent claims do not add additional clarity and, therefore, are also indefinite.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 25-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for purifying an anti-IL4Rα antibody or Dupilumab, does not reasonably provide enablement for any harvested antibody. The Specification does not enable any person skilled in the area to which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 732, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The breadth of claims 25-29 encompasses a method for producing an anti-IL4Rα antibody or antigen-binding fragment thereof by subjected any harvested antibody or antigen-binding fragment thereof to the remaining method steps resulting in a final product of purified anti-IL4Rα antibody while the breadth of claims 30-43 encompasses a method of subjecting any harvested antibody to the remaining method steps resulting in a final product of purified anti-IL4Rα antibody.
There are no working examples where a general monoclonal antibody undergoes the filtration process and results in a specific anti-IL4Rα or Dupilumab at the end of the process. There are also no working examples of anti-ILR4α antibodies being produced by these methods; the Cambridge dictionary (https://dictionary.cambridge.org/us/dictionary/english/producing) defines “producing” as “to make something or bring it into existence.” The method steps described are methods of purifying the antibody rather than producing it. Keszey, et al. (WO 2020200980 A1, FOR-IDS, filed 09/26/2023, hereinafter “Keszey”) provides a review of antibody purification methods and states that the antibodies are producing by recombinant DNA technology and then purified (pg. 1 lines 13-15). Keszey also teaches that the input immungloublin is the same as the output immunoglobulin that is eluted in the final step of purification (claim 1).
The direction and guidance coupled with the working examples of the application, however, are drawn only to demonstrating a collection of methods to purify anti-IL4Ra antibody, wherein said anti-IL4Ra antibody is Dupilumab (See enumerated examples, specifically 1, 17-18, 29-30, 65, 87, 106, 113, 124, 134, 139, 202).
The quantity experimentation would be considerable because, while the relative skill level in the art is high (PhD or MD), they would be required to ascertain which generic "harvested antibody" could undergo the claimed chromatography methods and pH changes to purify a specific anti-IL4Rα antibody. It would be extremely difficult without undue to experimentation to determine what antibodies could be anti-IL4Rα when exposed to the claimed methods. It would be impossible to use any harvested antibody as the input to the methods and result in purified anti-IL4Rα.
For the purposes of compact prosecution and applying prior art, the enabled methods of “purifying” rather than “producing” were searched.
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 1-4, 8-11, 30-33, and 37-43 are rejected under 35 U.S.C. 103 as being unpatentable over Keszey as evidenced by Le Floc’h, et al. (Allergy. 2020 May;75(5):1188-1204., hereinafter “Le Floc’h) and Kegg Drug ID: D10354 (available at https://www.genome.jp/dbget-bin/www_bget?dr:D10354 and published on the WayBack Machine April 22, 2015 at https://web.archive.org/web/20150422110706/http://www.genome.jp/dbget-bin/www_bget?dr:D10354, hereinafter “Kegg”) and in further view of GE Healthcare (Published 04/2010 and available at https://www.med.unc.edu/pharm/sondeklab/wp-content/uploads/sites/868/2018/10/Ion-exchange.pdf, hereinafter “GE”) as evidenced by Zou (AAPS J. 2023 Mar 23;25(3):31.) and further evidenced by Cytiva (MabSelect, Affinity Chromatography; available at https://cdn.cytivalifesciences.com/api/public/content/digi-13118-pdf?_gl=1*150hjlo*_gcl_au*MTQ0Mzc1OTg4Ni4xNzc3NTYzOTI4*_ga*MTYzMjI1MzA4OS4xNzc3NTYzOTI5*_ga_HDHKGPXE6G*czE3Nzc1NjM5MzAkbzEkZzAkdDE3Nzc1NjM5MzEkajU5JGwwJGgxODAwOTIwOTM3, published in 2020).
Regarding claims 1, 30, and 41-43, Keszey teaches a method of purifying an immunoglobulin (pg. 8 lines 1-3) from a cell culture fluid comprising the steps of: (1) subjecting harvested antibody to affinity chromatography (pg. 8 lines 6-7); (2) incubating the eluate from step (1) for virus inactivation at a low pH of 2.5 to 4.5 (pg. 9 lines 27-28); (3) performing cation exchange chromatography on elute from step (2) (pg. 9 line 30) in bind and elute mode (pg. 11, lines 23-24); (4) performing anion exchange chromatography on eluate from step (3) (pg. 9 line 31) in flow-through mode (pg. 12 lines 2-3); and (5) exposing the eluate from step (4) to nanofiltration (pg. 10 lines 1-2), which is a type of filtration that removes viruses (pg. 11 line 4). Keszey further teaches that the method of purifying immunoglobulins can be used to purify Dupilumab (pg. 19 line 10), as evidenced by Le Floc’h, Dupilumab is an IL-4Rα antibody (title). Kegg evidences that Instant SEQ ID NOs: 1-8 are the HCVR (1), LCVR (2), HCDR (3-5), and LCDR (6-8) of Dupilumab (sequence and see alignment below).
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Keszey does not teach adjusting the pH of the pooled Dupilumab from after viral inactivation to 5-8. However, GE teaches that for further purification using ion chromatography the virally inactivated pooled antibody needs to be at least 0.5-1 pH below the pI of the antibody for cation exchange (pg. 71 ¶4). Zou evidences that the pI of Dupilumab is 6.86 or 7.81 (depending on the model, Pg. 15, entry 31), hence the pH would be need to be adjusted to 5.86-6.81 for cation exchange.
It would have been prima facie obvious to one of ordinary skill in the art to have combined the teachings of Keszey for a method of purifying Dupilumab with the teachings of GE of the necessary pH required for cation exchange. GE provides motivation by teaching that for further purification using ion chromatography the virally inactivated pooled antibody needs to be at least 0.5-1 pH below the pI of the antibody for cation exchange (pg. 71 ¶4). One of skill in the art would have had a reasonable expectation of success in combining the teachings of Keszey and GE because they both teach cation exchange.
Regarding claims 2 and 31, Keszey teaches adding a flocculation-inducing compound to the cell culture fluid before purification (pg. 8 line 4).
Regarding claims 3 and 32, Keszey teaches that the flocculation step can include pH adaptation (pg. 23 lines 28-31). Keszey does not explicitly teach adjusting the antibody to a transient pH level of about 4-5.5. However, routine optimization of the pH during pre-treatment before affinity chromatography would have led to the claimed transient pH because Keszey teaches that the pre-treatment step can include pH adaptation (pg. 23 lines 28-31) for further downstream purification. The person of ordinary skill in the art would have found it obvious to optimize the transient pH to achieve the desired pH for downstream purification by starting with the pH after pre-treatment and optimizing until achieving the desired results.
Regarding claims 4 and 33, Keszey further teaches exposing the filtrate from step (5) in claim 1 to further processing by ultrafiltration/diafiltration (pg. 10 lines 3-4).
Regarding claims 8 and 37, Keszey teaches that the affinity chromatography is Protein A chromatography (pg. 9, line 8).
Regarding claims 9 and 38, Keszey teaches many Protein A resins that can be used for affinity chromatography, including MabSelect PrismATM (pg. 29 lines 25-31).
Regarding claims 10 and 39, Keszey teaches the MabSelect PrismATM Protein A resin which, as evidenced by Cytiva, is capable of receiving a load of at least 24 mg IgG/mL (pg. 9 Example).
Regarding claims 11 and 40, Keszey teaches the MabSelect PrismATM Protein A resin which, as evidenced by Cytiva, uses a buffer for loading that is at pH 7 (pg. 8 Example of suitable buffers).
Accordingly, the claimed inventions were prima facie obvious to one or ordinary skill in the art before the effective filing date, especially in the absence of evidence to the contrary.
Claims 5-7, 25-29, and 34-36 are rejected under 35 U.S.C. 103 as being unpatentable over Keszey as evidenced by Le Floc’h and Kegg and GE as evidenced by Zou and further evidenced by Cytiva as applied to claims 1-4, 8-11, 30-33, and 37-43 above, and further in view of Ambrožič, et al. (Biotechnol Bioeng. 2021 Feb;118(2):633-646., hereinafter “Ambrozic”).
As discussed above, claims 1-4, 8-11, 30-33, and 37-43 were rendered prima facie obvious over Keszey as evidenced by Le Floc’h and Kegg and GE as evidenced by Zou and further evidenced by Cytiva.
Regarding claims 5 and 34, Keszey and GE do not teach a diafiltration buffer having a pH between 4.0 and 4.5. However, Ambrozic teaches many diafiltration buffers with pHs ranging from 4.9-7.9 (Table S1) and that initial pH concertation is an optimizable parameter that significantly affects the permeate and retentate concentrations (pg. 635, column 1). Routine optimization of the initial DF buffer pH taught by Ambrozic would have led to the claimed DF buffer pH of 4.0-4.5 because Ambrozic teaches that the pH of the diafiltration buffer is adjustable (Table S1) and affects the final concentrations of antibodies after purification (pg. 635, column 1). The person of ordinary skill in the art would have found it obvious to optimize the starting DF buffer pH to achieve the desired final antibody concentration by starting with the buffers taught by Ambrozic and optimizing until achieving the desired results. One of skill in the art would have a reasonable expectation of success in using the DF buffers taught by Ambrozic in the method taught by Keszey because Keszey and Ambrozic teach diafiltration.
Regarding claims 6 and 35, Ambrozic teaches a UF/DF pooled antibody in the retentate/feed tank with a pH measured between 5.25 and 8.0 (Figure 3b).
Regarding claims 7 and 36, Ambrozic teaches DF buffers that contain 5mM of acetate (Table S1, buffers D5-D7).
Regarding claim 25, Keszey teaches a method of purifying an immunoglobulin (pg. 8 lines 1-3) from a cell culture fluid comprising the steps of: (1) subjecting harvested antibody to affinity chromatography (pg. 8 lines 6-7); (2) incubating the eluate from step (1) for virus inactivation (pg. 9 lines 27-28); (3) performing cation exchange chromatography on elute from step (2) (pg. 9 line 30) in bind and elute mode (pg. 11, lines 23-24); (4) performing anion exchange chromatography on eluate from step (3) (pg. 9 line 31) in flow-through mode (pg. 12 lines 2-3); (5) exposing the eluate from step (4) to nanofiltration (pg. 10 lines 1-2), which is a type of filtration that removes viruses (pg. 11 line 4); and (6) exposing the filtrate from step (5) to further processing by ultrafiltration/diafiltration (pg. 10 lines 3-4). Keszey further teaches that the method of purifying immunoglobulins can be used to purify Dupilumab (pg. 19 line 10), as evidenced by Le Floc’h, Dupilumab is an IL-4Rα antibody (title). Keszey does not teach that the DF step does not include the addition of arginine. However, Ambrozic teaches many DF buffers that do not include arginine (Table S1).
Regarding claim 26, Keszey and GE do not teach a diafiltration buffer having a pH between 4.0 and 4.5. However, Ambrozic teaches many diafiltration buffers with pHs ranging from 4.9-7.9 (Table S1) and that initial pH concertation is an optimizable parameter that significantly affects the permeate and retentate concentrations (pg. 635, column 1). Routine optimization of the initial DF buffer pH taught by Ambrozic would have led to the claimed DF buffer pH of 4.0-4.5 because Ambrozic teaches that the pH of the diafiltration buffer is adjustable (Table S1) and affects the final concentrations of antibodies after purification (pg. 635, column 1). The person of ordinary skill in the art would have found it obvious to optimize the starting DF buffer pH to achieve the desired final antibody concentration by starting with the buffers taught by Ambrozic and optimizing until achieving the desired results
Regarding claim 27, Ambrozic teaches DF buffers that contain 5mM of acetate (Table S1, buffers D5-D7).
Regarding claim 28, Ambrozic teaches a UF/DF pooled antibody in the retentate/feed tank with a pH measured between 5.25 and 8.0 (Figure 3b).
Regarding claim 29, , Ambrozic teaches using a Pellicon 3 cassette with a 30 kD membrane for UF/DF tangential flow filtration (pg. 636 column 1).
Accordingly, the claimed inventions were prima facie obvious to one or ordinary skill in the art before the effective filing date, especially in the absence of evidence to the contrary.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-11 and 25-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-11, 14, 29-36, 38-44, and 50 of copending Application No. 18/175,809 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘809 claims would render the instant claims prima facie obvious.
Regarding claim 1, the reference claim 1 recites a method comprising the steps of: (a) subjecting harvested Dupilumab to affinity chromatography; (b) subjecting said Dupilumab pooled from eluate of step (a) to viral inactivation at a pH from about 3 to about 4 and then adjusting the pH to from about 5 to about 8; (c) subjecting said Dupilumab pooled from step (b) to anion exchange chromatography in flowthrough mode; (d) subjecting said Dupilumab pooled from flowthrough fractions of step (c) to cation exchange chromatography in bind and elute mode; (e) subjecting said Dupilumab pooled from eluate of step (d) to hydrophobic interaction chromatography in flowthrough mode; and (f) subjecting said Dupilumab pooled from flowthrough fractions of step (e) to virus retentive filtration to produce Dupilumab.
The reversing or changing the order of process steps is obvious unless there is some unexpected result in doing so. See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.) See MPEP 2144.04, Section IV(C).
Regarding claim 2, reference claim 2 recites that the method further comprises a harvest pre-treatment step.
Regarding claim 3, reference claim 3 recites that the harvest pre-treatment step includes adjusting said Dupilumab to a transient pH level from about 4 to 5.5.
Regarding claim 4, reference claim 5 recites that the method further comprises subjecting said Dupilumab to ultrafiltration and diafiltration (UF/DF) after step (f).
Regarding claim 5, reference claim 6 recites that the UF/DF includes a diafiltration buffer having a pH between 4.0 and 4.5.
Regarding claim 6, reference claim 7 recites that the concentrated Dupilumab pool following UF/DF has a pH of about 5.3.
Regarding claim 7, reference claim 8 recites that the UF/DF includes a diafiltration buffer comprising between about 4 mM acetate and about 6 mM acetate.
Regarding claim 8, reference claim 9 recites that the affinity chromatography is Protein A chromatography.
Regarding claim 9, reference claim 10 recites that the Protein A resin is selected from the group consisting of MabSelect PrismA, MabSelect SuRe, MabSelect SuRe LX, MabSelect, MabSelect SuRe pcc, MabSelect Xtra, rProtein A Sepharose, ProSep HC, ProSep Ultra, ProSep Ultra Plus, MabCapture, and Amsphere A3.
Regarding claim 10, reference claim 11 recites that the Protein A resin is selected that is capable of receiving a load at a concentration above 55 g/L.
Regarding claim 11, reference claim 14 recites that the Protein A column load pH is between 6 and 8.
Regarding claim 25, reference claim 29 recites a method for producing an anti-IL4Ra antibody, comprising (a) subjecting a harvested antibody to affinity chromatography; (b) subjecting said antibody pooled from eluate of step (a) to viral inactivation; (c) subjecting said antibody pooled from step (b) to anion exchange chromatography in flowthrough mode; (d) subjecting said pooled from flowthrough fractions of step (c) to cation exchange chromatography in bind and elute mode; (e) subjecting said antibody pooled from eluate of step (d) to hydrophobic interaction chromatography in flowthrough mode; (f) subjecting said antibody pooled from flowthrough fractions of step (e) to virus retentive filtration; and (g) subjecting said antibody pooled from step (f) to ultrafiltration and diafiltration (UF/DF) to produce an anti-IL4Rα antibody, wherein said UF/DF step does not include addition of arginine.
The reversing or changing the order of process steps is obvious unless there is some unexpected result in doing so. See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.) See MPEP 2144.04, Section IV(C).
Regarding claim 26, reference claim 30 recites that the diafiltration buffer has a pH of 4.0 to 4.5.
Regarding claim 27, reference claim 31 recites that the diafiltration buffer comprises between about 4 mM acetate and about 6 mM acetate
Regarding claim 28, reference claim 32 recites that the concentrated pool following UF/DF has a pH of about 5.3.
Regarding claim 29, reference claim 33 recites that the UF/DF step comprises a membrane filter device selected from the group consisting of Pellicon 2, Pellicon 3 cassettes with 10 kD, 30 kD or 50 kD membranes, Kvick 10 kD, 30 kD or 50 kD membrane cassettes, and Centramate and Centrasette 10 kD, 30 kD or 50 kD cassettes.
Regarding claim 30, reference claim 34 recites a method comprising the steps of: (a) subjecting a harvested antibody to affinity chromatography; (b) subjecting said antibody pooled from eluate of step (a) to viral inactivation at a pH from about 3 to about 4 and then adjusting the pH to from about 5 to about 8; (c) subjecting said antibody pooled from step (b) to anion exchange chromatography in flowthrough mode; (d) subjecting said antibody pooled from flowthrough fractions of step (c) to cation exchange chromatography in bind and elute mode; (e) subjecting said antibody pooled from eluate of step (d) to hydrophobic interaction chromatography in flowthrough mode; and (f) subjecting said antibody pooled from flowthrough fractions of step (e) to virus retentive filtration to produce an anti-IL4Rα antibody.
The reversing or changing the order of process steps is obvious unless there is some unexpected result in doing so. See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.) See MPEP 2144.04, Section IV(C).
Regarding claim 31, reference claim 35 recites that the method further comprises a harvest pre-treatment step.
Regarding claim 32, reference claim 36 recites that the harvest pre-treatment step includes adjusting said Dupilumab to a transient pH level from about 4 to 5.5.
Regarding claim 33, reference claim 38 recites that the method further comprises subjecting said Dupilumab to ultrafiltration and diafiltration (UF/DF) after step (f).
Regarding claim 34, reference claim 39 recites that the UF/DF includes a diafiltration buffer having a pH between 4.0 and 4.5.
Regarding claim 35, reference claim 40 recites that the concentrated Dupilumab pool following UF/DF has a pH of about 5.3.
Regarding claim 36, reference claim 41recites that the UF/DF includes a diafiltration buffer comprising between about 4 mM acetate and about 6 mM acetate
Regarding claim 37, reference claim 42 recites that the affinity chromatography is Protein A chromatography.
Regarding claim 38, reference claim 43 recites that the Protein A resin is selected from the group consisting of MabSelect PrismA, MabSelect SuRe, MabSelect SuRe LX, MabSelect, MabSelect SuRe pcc, MabSelect Xtra, rProtein A Sepharose, ProSep HC, ProSep Ultra, ProSep Ultra Plus, MabCapture, and Amsphere A3.
Regarding claim 39, reference claim 44 recites that the Protein A resin is selected that is capable of receiving a load at a concentration above 55 g/L.
Regarding claim 40, reference claim 47 recites that the Protein A column load pH is between 6 and 8.
Regarding claims 41-43, reference claim 50 recites that the anti-IL-4Rα antibody is Dupilumab. Instant SEQ ID NOs: 1-8 are the sequence for Dupilumab (see alignment above).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/115,354 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘354 claims would render the instant claims prima facie obvious.
Regarding claim 1, the reference claim 1 recites a method comprising the steps of (a) culturing cells expressing Dupilumab using a cell culture medium comprising ornithine at between about 0.09 and about 0.9 mM and/or putrescine at between about 0.20 mM and about 0.9 mM, (b) harvesting said cells by centrifugation to separate cell debris from clarified media comprising Dupilumab; (c) subjecting said clarified media to affinity chromatography; (d) subjecting said Dupilumab pooled from eluate of step (c) to viral inactivation at a pH from about 3 to about 4 and then adjusting the pH to from about 5 to about 8; (e) subjecting said Dupilumab pooled from step (d) to anion exchange chromatography in flowthrough mode; (f) subjecting said Dupilumab pooled from flowthrough fractions of step (e) to cation exchange chromatography in bind and elute mode; (g) subjecting said Dupilumab pooled from eluate of step (f) to hydrophobic interaction chromatography in flowthrough mode; (h) subjecting said Dupilumab pooled from flowthrough fractions of step (g) to virus retentive filtration to produce Dupilumab; and (i) collecting said Dupilumab. Dupilumab is an anti-IL4Rα antibody.
The reversing or changing the order of process steps is obvious unless there is some unexpected result in doing so. See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.) See MPEP 2144.04, Section IV(C).This is a provisional nonstatutory double patenting rejection.
Claims 1-11 and 35-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 21-22, 29-30, 33-43, and 53 of copending Application No. 18/175, 914 (reference application) and in further view of Keszey. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘914 claims would render the instant claims prima facie obvious.
Regarding claim 1, reference claim 1 recites a method comprising the steps of: (a) subjecting harvested Dupilumab to affinity chromatography; (b) subjecting said Dupilumab pooled from eluate of step (a) to viral inactivation at a pH from about 3 to about 4 and then adjusting the pH to from about 5 to about 8; (c) subjecting said Dupilumab pooled from step (b) to mixed-mode chromatography; (d) subjecting said Dupilumab pooled from step (c) to anion exchange chromatography in flowthrough mode; and (e) subjecting said Dupilumab pooled from flowthrough fractions of step (d) to virus retentive filtration to produce Dupilumab. The reference claims do not recite cation exchange chromatography. However, Keszey teaches that further purification steps may be performed after initial affinity chromatography, including cation exchange chromatography (Pg. 9 lines 22-25).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the invention to have substituted the mix-mode chromatography recited by the reference claims for the cation exchange chromatography taught by Keszey. Kesey teaches that further purification steps are optimizable and interchangeable (Pg. 9 lines 22-25). One of skill in the art would have a reasonable expectation of success in substituting the mix-mode chromatography taught by the reference claims for the cation chromatography taught by Keszey because both teach methods of purifying antibodies.
Regarding claim 2, reference claim 2 recites that the method further comprises a harvest pre-treatment step.
Regarding claim 3, reference claim 3 recites that the harvest pre-treatment step includes adjusting said Dupilumab to a transient pH level from about 4 to 5.5.
Regarding claim 4, reference claim 4 recites that the method further comprises subjecting said Dupilumab to ultrafiltration and diafiltration (UF/DF) after step (f).
Regarding claim 5, reference claim 5 recites that the UF/DF includes a diafiltration buffer having a pH between 4.0 and 4.5.
Regarding claim 6, reference claim 6 recites that the concentrated Dupilumab pool following UF/DF has a pH of about 5.3.
Regarding claim 7, reference claim 7 recites that the UF/DF includes a diafiltration buffer comprising between about 4 mM acetate and about 6 mM acetate
Regarding claim 8, reference claim 8 recites that the affinity chromatography is Protein A chromatography.
Regarding claim 9, reference claim 9 recites that the Protein A resin is selected from the group consisting of MabSelect PrismA, MabSelect SuRe, MabSelect SuRe LX, MabSelect, MabSelect SuRe pcc, MabSelect Xtra, rProtein A Sepharose, ProSep HC, ProSep Ultra, ProSep Ultra Plus, MabCapture, and Amsphere A3.
Regarding claim 10, reference claim 10 recites that the Protein A resin is selected that is capable of receiving a load at a concentration above 55 g/L.
Regarding claim 11, reference claim 11 recites that the Protein A column load pH is between 6 and 8.
Regarding claim 25, reference claims 21-22 and 30 recite a method comprising the steps of: (a) culturing cells expressing Dupilumab; (b) subjecting said cells to transient pH levels from about 4 to 5.5, then raising pH levels to from about 5.5 to 6.5; (c) harvesting said cells by centrifugation to separate cell debris from clarified media comprising said Dupilumab; (d) subjecting said clarified media to affinity chromatography; (e) subjecting said Dupilumab pooled from eluate of step (d) to viral inactivation at a pH from about 3 to about 4 and then adjusting the pH to from about 5 to about 8; (f) subjecting said Dupilumab pooled from step (e) to mixed-mode chromatography in flowthrough mode; (g) subjecting said Dupilumab pooled from flowthrough fractions of step (f) to anion exchange chromatography in flowthrough mode; and (h) subjecting said Dupilumab pooled from flowthrough fractions of step (g) to virus retentive filtration; and (i) subjecting said antibody or antigen-binding fragment thereof pooled from step (h) to ultrafiltration and diafiltration (UF/DF) to produce an anti-IL4Rα antibody, wherein said UF/DF step does not include addition of arginine.
Regarding claim 26, reference claim 5 recites that the UF/DF includes a diafiltration buffer having a pH between 4.0 and 4.5.
Regarding claim 27, reference claim 7 recites that the UF/DF includes a diafiltration buffer comprising between about 4 mM acetate and about 6 mM acetate.
Regarding claim 28, reference claim 6 recites that the concentrated Dupilumab pool following UF/DF has a pH of about 5.3.
Regarding claim 29, reference claim 29 recites that the UF/DF step comprises a membrane filter device selected from the group consisting of Pellicon 2, Pellicon 3 cassettes with 10 kD, 30 kD or 50 kD membranes, Kvick 10 kD, 30 kD or 50 kD membrane cassettes, and Centramate and Centrasette 10 kD, 30 kD or 50 kD cassettes.
Regarding claim 30, reference claim 33 recites a method comprising the steps of: (a) subjecting a harvested antibody to affinity chromatography; (b) subjecting said antibody pooled from eluate of step (a) to viral inactivation at a pH from about 3 to about 4 and then adjusting the pH to from about 5 to about 8; (c) subjecting said antibody pooled from step (b) to mixed-mode chromatography; (d) subjecting said antibody pooled from step (c) to anion exchange chromatography in flowthrough mode; and (e) subjecting said antibody pooled from flowthrough fractions of step (d) to virus retentive filtration to produce an anti-IL4Rα antibody. The reference claims do not recite cation exchange chromatography. However, Keszey teaches that further purification steps may be performed after initial affinity chromatography, including cation exchange chromatography (Pg. 9 lines 22-25).
Regarding claim 31, reference claim 34 recites that the method further comprises a harvest pre-treatment step.
Regarding claim 32, reference claim 35 recites that the harvest pre-treatment step includes adjusting said Dupilumab to a transient pH level from about 4 to 5.5.
Regarding claim 33, reference claim 36 recites that the method further comprises subjecting said Dupilumab to ultrafiltration and diafiltration (UF/DF) after step (f).
Regarding claim 34, reference claim 37 recites that the UF/DF includes a diafiltration buffer having a pH between 4.0 and 4.5.
Regarding claim 35, reference claim 38 recites that the concentrated Dupilumab pool following UF/DF has a pH of about 5.3.
Regarding claim 36, reference claim 39 recites that the UF/DF includes a diafiltration buffer comprising between about 4 mM acetate and about 6 mM acetate
Regarding claim 37, reference claim 40 recites that the affinity chromatography is Protein A chromatography.
Regarding claim 38, reference claim 41 recites that the Protein A resin is selected from the group consisting of MabSelect PrismA, MabSelect SuRe, MabSelect SuRe LX, MabSelect, MabSelect SuRe pcc, MabSelect Xtra, rProtein A Sepharose, ProSep HC, ProSep Ultra, ProSep Ultra Plus, MabCapture, and Amsphere A3.
Regarding claim 39, reference claim 42 recites that the Protein A resin is selected that is capable of receiving a load at a concentration above 55 g/L.
Regarding claim 40, reference claim 43 recites that the Protein A column load pH is between 6 and 8.
Regarding claims 41-43, reference claim 53 recites that the anti-IL-4Rα antibody is Dupilumab. Instant SEQ ID NOs: 1-8 are the sequence for Dupilumab (see alignment above).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
NO CLAIMS ARE ALLOWED
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/CASSANDRA SENN GRIZER/ Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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