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 .
Status of the Application
1. Claims 1-14, 17-26, 29-47, and 50-54 are pending and subject to examination on the merits. Claims 51-54 are withdrawn from consideration as being drawn to non-elected subject matter. Claims 1-14, 17-26, 29-47, and 50 are currently under examination.
Priority
2. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 63/315,897 filed 02 March 2022.
Election/Restrictions
3. Claims 51-54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 22 December 2025.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted on 27 September 2023 and 05 January 2026 have been considered by the examiner. See initialed and signed PTO/SB/08’s.
Drawings
5. 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.
6. The drawings are objected to because: (a) Figure 5 does not include units for the second panel x-axis above the 15 mg/mL insulin concentration (0, 5, 10, 15); (b) there are no units associated with Figure 19, x-axis, “Time Point”; (c) there are no units associated with Figure 21, 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”; (l) 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
7. 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.
8. The use of the term Millistak+™ (paragraph 0344), MabSelect™ (paragraph 0349), ProSep™ (paragraph 0349), MabCapture™ (paragraph 0349), Poros™ (paragraph 0381), Capto™ (paragraph 0381), Capto™ (paragraph 0399), Poros™ (paragraph 0399), Bio-Gel™ (paragraph 0433), Capto™ (paragraph 0638), MabSelect™ (p. 216, enumerated example 270), MabCapture™ p. 216, enumerated example 270), MabSelect™ (p. 218, enumerated example 287), MabCapture™ (p. 218, enumerated example 287), Capto™ (p. 218, enumerated example 288), Poros™ (p. 218, enumerated example 289), Capto™ (p. 218, enumerated example 291), Fractogel™ (p. 218, enumerated example 291), Capto™ (p. 218, enumerated example 292), Fractogel™ (p. 219, enumerated example 293), Capto™ (p. 219, enumerated example 297), Fractogel™ (p. 219, enumerated example 297), MabSelect™ (p. 223, enumerated example 327), Capto™ (p. 224, enumerated example 328), Fractogel™ (p. 224, enumerated example 328), Sartobind™ (p. 224, enumerated example 328), Capto™ (p. 224, enumerated example 329), MabSelect™ (p. 227, enumerated example 353), Capto™ (p. 229, enumerated example 378), MabSelect™ (p. 233, enumerated example 395), Capto™ (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 ™, 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
9. Claim 12 is objected to because of the following informalities: “HIC” should be defined; to mitigate this, add “HIC” to claim 1 after hydrophobic interaction chromatography (line 7). Appropriate correction is required.
10. Claim 13 is objected to because of the following informalities: “PLBD2” should be defined before the abbreviation is used. Appropriate correction is required.
11. Claim 14 is objected because of the following informalities: “a Protein A…” should be “the Protein A…,” since it is dependent on claim 9, which recites “Protein A…”. Appropriate correction is required.
12. Claim 44 is objected because of the following informalities: “a Protein A resin is selected that is capable…” should be changed to “a selected Protein A resin is…” to improve grammar. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
13. 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.
Enablement:
14. Claims 34-47 and 50 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 a method comprising the steps of: (a) subjecting a harvested anti-IL4Rα or Dupilumab to affinity chromatography; (b) subjecting said anti-IL4Rα or Dupilumab pooled from eluate of step (a) to viral inactivation at a pH from about 3-4 and then adjusting the pH to 5-8; (c) subjecting said antibody pooled from step (b) to anion exchange chromatography in flowthrough mode; (d) subjecting said antibody pooled from flowthrough fraction of step (c) to cation exchange chromatography in bind and elute mode; (e) subjecting said anti-IL4Rα or Dupilumab of step (d) to hydrophobic interaction chromatography in flowthrough mode; and (f) subjecting said anti-IL4Rα or Dupilumab fractions of step (e) to virus retentive filtration to produce an anti-IL4Rα or Dupilumab, does not reasonably provide enablement for any “harvested antibody” (claim 34, line 1) undergoing the claimed said method to produce an anti-IL4Rα antibody. There are no working examples where a general monoclonal antibody undergoes the filtration process and produces a specific anti-IL4Rα or Dupilumab at the end of the process. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims without significant undue experimentation.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states:
"Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims in their broadest are drawn to 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 3-4 and then adjusting the pH to 5-8; (c) subjecting said antibody pooled from step (b) to anion exchange chromatography in flowthrough mode; (d) subjecting said antibody pooled from flowthrough fraction of step (c) to cation exchange chromatography in bind and elute mode; (e) subjecting said antibody of step (d) to hydrophobic interaction chromatography in flowthrough mode; and (f) subjecting said antibody fractions of step (e) to virus retentive filtration to produce an anti-IL4Rα. The direction and guidance coupled with the working examples of the application, however, are drawn only to demonstrating a collection of methods to obtain anti-IL4Rα antibody, wherein said anti-IL4Rα 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 and become a specific anti-IL4Rα antibody. It would be extremely difficult to determine what antibodies could become an ant-IL4Rα when exposed to the claimed methods. It would be impossible to use any harvested antibody as the input to the methods and result an anti-IL4Rα.
Claim Rejections - 35 USC § 112(b)
15. 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.
16. Claims 3, 10, 13, 17, 20-23, 34-47 and 50 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.
17. Claim 3 recites the limitation “transient pH” in line 2. It is unclear what transient is in reference to, i.e. how long is transient and from what pH is this transient pH adjusted from and subsequently back to? For examination purposes, “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 of this target (about 4-5.5).
18. The use of the term MabSelect™, ProSep™, MabCapture™ in claim 10, 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 ™, 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.
19. Claim 13 recites the limitation "PLB2" in lines 1-3 and 5. There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not recite PLBD2.
20. Claim 17 recites the limitation “transient pH” in line 2. It is unclear what transient is in reference to, i.e. how long is transient and from what pH is this transient pH adjusted from? For examination purposes, “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).
21. The use of the term MabSelect™, ProSep™, and MabCapture™ in claim 20, 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 ™, 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.
22. The use of the term Poros™, Capto™, Fractogel™, and Sartobind™ in claim 20, 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 ™, 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.
23. The use of the term Poros™, Capto™, Toyopearl GigaCap™, Fractogel™, and Sartobind™ in claim 21, 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 ™, 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.
24. The use of the term Poros™, Capto™, and Fractogel™ in claim 22, 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 ™, 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.
25. The use of the term LifeAssure™ in claim 23, 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 ™, 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.
26. The use of the term Capto™, Fractogel™, and Macro-Prep™ in claim 23, which is a trade name or a mark used in commerce, has been noted in this application. The 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 ™, 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.
27. The use of the term MabSelect™, ProSep™, and MabCapture™ in claim 23, which is a trade name or a mark used in commerce, has been noted in this application. The 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 ™, 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.
28. Regarding claim 34, 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). Claims 35-47 and 50 are included in the instant rejection, since they do not mitigate the issue.
29. Claim 46 recites the limitation "PLBD2" in lines 1-3 and 5. There is insufficient antecedent basis for this limitation in the claim. Claim 34 does not recite PLBD2.
Claim Rejections - 35 USC § 103
30. 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.
31. Claims 1-3, 5, 9, 17-19, 34-36, 38, 42, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Keszey and Suto (Keszey and Suto, 2021, WO 2020200980 A1—cited on the IDS filed 27 September 2023), as evidenced by Thermo (Thermo, 2007, “Ion Exchange Chromatography,” downloaded 30 April 2026 from <https://documents.thermofisher.com/TFS-Assets/LSG/Application-Notes/TR0062-Ion-exchange-chrom.pdf> as a PDF--cited herein), as evidenced by Zou et al (Zou et al., 2023, The AAPS Journal—cited herein), as evidenced by Biorad (Biorad, 2026, “Introduction to Multimodal or Mixed-Mode Chromatography,” downloaded 22 April 2026 from < https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG44> as a PDF—cited herein), and as evidenced by Korneyeva and Rosenthal, 2005, Methods in Molecular Biology—cited herein).
Regarding the claims 1-3, 5, 9, 17-19, 34-36, 38, 42, and 50 drawn to a method comprising the steps of: (a) subjecting harvested Dupilumab (claims 1, 17, and 50) or anti-IL4Rα antibody to affinity chromatography, wherein said affinity chromatography is Protein A chromatography (claims 9, 17, and 42); (b) subjecting said Dupilumab pooled from eluate of step (a) to viral inactivation at a pH from about 3-4 (or 4-5.5; claim 17) and adjusting the pH from about 5 to about 8 (or 5.5-6.5; claim 17); (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, Keszey and Suto teach (1) exposing filtrate containing an immunoglobulin to an affinity chromatography medium, (2) eluting the immunoglobulin from the affinity chromatography resin using an elution buffer with a pH of 2.5-4.5 (p. 8, lines 6-7 and 10-11), (3) incubating the eluate for virus inactivation at a low pH value of 2.5-4.5 for 10 mins, (4) performing a cation exchange chromatography, (where the pH of the viral inactivated Dupilumab needs to be within 1 pH unit of the pI as evidenced by Thermo to perform ion exchange chromatograph (p. 1, paragraph 1); where specifically, the calculated pI of Dupilumab is 6.86 or 7.81 (depending on the model), as evidenced by Zou (p. 15, entry 31), hence the pH would be adjusted to 5.86-6.81 (anion) or 7.86 to 8.96 (cation); (5) performing mixed-mode chromatography (where mixed-mode chromatography can be any mix of cation, anion, and/or hydrophobic interaction chromatography, as evidenced by BioRad, p. 4-5, bullet list) or an anion exchange chromatography, (6) exposing the eluate to one or more further processing steps and subsequent nanofiltration (where Korneyeva and Rosenthal evidence that virus removal is achieved via nanofiltration (title, paragraph 1, line 1), and (7) exposing the filtrate to ultrafiltration/diafiltration (p. 9,line 27-10, line 4), wherein said immunoglobulin can be dupilumab (p. 19, line 10), wherein the cation exchange chromatography is performed in binding mode, and anion exchange chromatography is performed in flow-through mode, and changing of the polishing steps is a frequently applied equivalent (p. 11, lines 13-15, Fig. 1B). Further, 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 claims 2, 17, and 35, drawn to a harvest pre-treatment step prior to affinity chromatography, Keszey and Suto teaches cleaning steps preceding the initial affinity chromatography steps, specifically utilizing flocculation and filtration to improve the quality of the eluted immunoglobulin (abstract). Regarding claims 3, 17, and 36, drawn to adjusting the pH to about 4-5.5, Keszey and Suto teaches that flocculation can include pH adaption (p. 23, line 32) to adjust the pH of the culture fluid to be less than the pI (isoelectric point) of the antibody to facilitate a flocculation step utilizing a cationic electrolyte to rid the culture of impurities while leaving the antibody in the solution (p. 24, lines 4-8), where specifically, the calculated pI of Dupilumab is 6.86 or 7.81 (depending on the model), as evidenced by Zou (p. 15, entry 31). Therefore, adjusting the pH to about 4-5.5 would be envisaged by Keszey and Suto, since they teach the adjustment of the pH of the culture fluid below that of the pI of the immunoglobulin. Additionally, the MPEP recites, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).” (See MPEP 2144.05 I). Regarding claims 5 and 38, drawn to subjecting the Dupilumab to ultrafiltration and diafiltration after viral retentive filtering, Keszey and Suto teaches step (7) exposing the filtrate to ultrafiltration/diafiltration (p. 9,line 27-10, line 4). Regarding claims claims 9 and 42, drawn to the affinity chromatography being Protein A chromatography, Keszey and Suto teach a preferred embodiment where the affinity chromatography is a Protein A chromatography (p. 9, lines 8-10).
Keszey and Suto do not expressly teach the specific pH ranges for viral inactivation and pre-treatments or the exact ordering for the subsequent polishing chromatography steps (i.e. anion exchange, cation exchange, and hydrophobic interaction). However, for the reasons listed above, Keszey and Suto still obviate the claims because they teach overlapping pH ranges for viral inactivation and subsequent chromatography (See MPEP 2144.05 I). Additionally, Keszey and Suto still obviate the claims drawn to the re-ordering of the polishing chromatography steps, as stated above, because the order of steps is obvious according to the MPEP (See MPEP 2144.04, Section IV(C)). Last, Keszey and Suto do not teach a specific working embodiment of Dupilumab; however Dupilumab is listed as a possible IgG antibody to utilize in the methods as stated above; therefore, the utilization of Dupilumab is envisaged by Keszey and Suto.
Therefore, it 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 to utilize the envisaged ranges of Keszey and Suto and reorder the steps of downstream polishing to produce dupilumab for manufacture. One would be motivated to combine these teachings to arrive at the instant claims to increase the purity of dupilumab as taught by Keszey and Suto (abstract). There would be reasonable expectation of success, yielding no surprising results when optimizing pH ranges and re-ordering polishing chromatography steps to produce a dupilumab, since Keszey and Suto teach the purification of IgG antibodies, such as Dupilumab, and the optimization of their methods would be obvious to a person having ordinary skill in the art.
32. Claims 4 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Keszey and Suto (Keszey and Suto, 2021, WO 2020200980 A1—cited on the IDS filed 27 September 2023), as evidenced by Thermo (Thermo, 2007, “Ion Exchange Chromatography,” downloaded 30 April 2026 from <https://documents.thermofisher.com/TFS-Assets/LSG/Application-Notes/TR0062-Ion-exchange-chrom.pdf> as a PDF--cited herein), as evidenced by Zou et al (Zou et al., 2023, The AAPS Journal—cited herein), as evidenced by Biorad (Biorad, 2026, “Introduction to Multimodal or Mixed-Mode Chromatography,” downloaded 22 April 2026 from < https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG44> as a PDF—cited herein), and as evidenced by Korneyeva and Rosenthal, 2005, Methods in Molecular Biology—cited herein) in further view of Yang et al (Yang et al., 2017, Biotechnology and Bioengineering—cited herein).
The teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal are discussed above and incorporated into the instant rejection.
Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal does not teach a concentration of 4-12 g/L of Dupilumab before viral retentive filtration (claims 4 and 37). Yang et al. teaches that the typical concentration of a monoclonal antibody prior to ultrafiltration/nanofiltration and after chromatography is 5-10 g/L (p. 2045, “Problem Domain,” lines 1-3).
Therefore, it 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 combine the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and Yang et al. to utilize a concentration of 4-12 g/L of Dupilumab before viral rententive filtration because it is a typical monoclonal antibody concentration entering the final steps as taught by Yang et al. (p. 2045, “Problem Domain,” lines 1-2). One would be motivated to combine these teachings to arrive at the instant claims to produce monoclonal antibodies to treat chronic conditions as taught by Yang et al (p. 2043, “Introduction,” lines 1-3). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and Yang et al. to utilize a concentration of 4-12 g/L entering the final filtration steps of the manufacture process, since Yang et al. teaches that 5-10 g/L is a common concentration to utilize.
33. Claims 7, 24-25, 29, 32-33, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Keszey and Suto (Keszey and Suto, 2021, WO 2020200980 A1—cited on the IDS filed 27 September 2023), as evidenced by Thermo (Thermo, “Ion Exchange Chromatography,” downloaded 30 April 2026 from <https://documents.thermofisher.com/TFS-Assets/LSG/Application-Notes/TR0062-Ion-exchange-chrom.pdf> as a PDF--cited herein), as evidenced by Zou et al (Zou et al., 2023, The AAPS Journal—cited herein), as evidenced by Biorad (Biorad, 2026, “Introduction to Multimodal or Mixed-Mode Chromatography,” downloaded 22 April 2026 from < https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG44> as a PDF—cited herein), and as evidenced by Korneyeva and Rosenthal, 2005, Methods in Molecular Biology—cited herein) in further view of Ambrozic et al (Ambrozic et al., 2020, Biotechnology and Bioengineering—cited herein).
The teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal are discussed above and incorporated into the instant rejection.
Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal do not teach a Dupilumab pool following UF/DF with a pH of about 5.3 (claim 7, 32, and 40), a UF/DF buffer that does not include the addition of arginine (claims 25 and 29), and a membrane filter device Pellicon™ 3 cassette with 30kD membrane (claims 24 and 33).
Regarding claims 7, 32, and 40 drawn to a UF/DF pooled Dupilumab with a pH of about 5.3, Ambrozic et al. teaches a UF/DF pooled antibody in the retentate/feed tank with a pH measured between 5.25 and 8.0 (Figure 3(b)). Regarding claims 25 and 29, drawn to a UF/DF buffer without arginine, Ambrozic et al. teaches ten formulations of buffers that do not contain arginine (See Table S1). Regarding claims 24 and 33, drawn to the utilization of a membrane filter device, specifically the Pellicon™ 3 cassette with a 30kD membrane, Ambrozic et al. teaches Pellicon™ 3 tangential flow filtration cassette utilizing Ultracel™ UF membrane of 30kDa molecular weight cutoff (p. 636, “Materials and Methods,” paragraph 1).
Therefore, it 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 combine the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and Ambrozic et al. to utilize UF/DF to concentrate Dupilumab because UF/DF operations are employed for achieving the desired therapeutic monoclonal antibody formulation as taught by Ambrozic et al (p. 633, abstract, line 1). One would be motivated to combine these teachings to arrive at the instant claims to produce a high-concentration protein formulation to enable higher dose requirements and/or subcutaneous administrations as taught by Ambrozic et al (p. 633, “Introduction end of paragraph 1-beginning of paragraph 2). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and Ambrozic et al. to produce a pooled Dupilumab by UF/DF, since Ambrozic et al. teaches the methods to produce monoclonal antibodies utilizing UF/DF as an end step to concentrate.
34. Claims 10-11, 14, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Keszey and Suto (Keszey and Suto, 2021, WO 2020200980 A1—cited on the IDS filed 27 September 2023), as evidenced by Thermo (Thermo, “Ion Exchange Chromatography,” downloaded 30 April 2026 from <https://documents.thermofisher.com/TFS-Assets/LSG/Application-Notes/TR0062-Ion-exchange-chrom.pdf> as a PDF--cited herein), as evidenced by Zou et al (Zou et al., 2023, The AAPS Journal—cited herein), as evidenced by Biorad (Biorad, 2026, “Introduction to Multimodal or Mixed-Mode Chromatography,” downloaded 22 April 2026 from < https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG44> as a PDF—cited herein), and as evidenced by Korneyeva and Rosenthal, 2005, Methods in Molecular Biology—cited herein) in further view of cytiva (cytiva, 2020, MabSelect, downloaded from <https://cdn.cytivalifesciences.com/api/public/content/digi-13118-pdf?_gl=1*150hjlo*_gcl_au*MTQ0Mzc1OTg4Ni4xNzc3NTYzOTI4*_ga*MTYzMjI1MzA4OS4xNzc3NTYzOTI5*_ga_HDHKGPXE6G*czE3Nzc1NjM5MzAkbzEkZzAkdDE3Nzc1NjM5MzEkajU5JGwwJGgxODAwOTIwOTM3 > on 01 May 2026—cited herein).
The teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal are discussed above and incorporated into the instant rejection.
Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal do not teach the utilization of MabSelect™ (claim 10), a load concentration of at least 55 g/L (claim 11), and a load pH is between 6-8 (claims 14 and 47).
Regarding claim 10, drawn to the utilization of a MabSelect™ resin, cytiva teaches MabSelect™ as a resin in protein A chromatography (Title; p. 3, Description). Regarding claim 11, drawn to a load concentration of at least 55 g/L, cytiva teaches a load concentration of 24 mg IgG/mL originating from CHO cells in an Example (p. 9, Example). Regarding claims 14 and 47, drawn to a load pH between 6-8, cytiva teaches loading in the presence of Buffer A, which has a pH of 7 (p. 8, “Example of suitable buffers”).
Therefore, it 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 combine the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and cytiva to utilize MabSelect™ resin as a protein A resin to produce Dupilumab because excellent purification can be achieved in one step (p. 3, Descripiton, paragraph 2). One would be motivated to combine these teachings to arrive at the instant claims to purify monoclonal antibodies at a process-scale with high capacity and low ligand leakage (p. 3, Description). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and cytiva, since cytiva demonstrates the utilization of MabSelect™ resins during Protein A purification of monoclonal antibodies.
35. Claims 13, 26, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Keszey and Suto (Keszey and Suto, 2021, WO 2020200980 A1—cited on the IDS filed 27 September 2023), as evidenced by Thermo (Thermo, “Ion Exchange Chromatography,” downloaded 30 April 2026 from <https://documents.thermofisher.com/TFS-Assets/LSG/Application-Notes/TR0062-Ion-exchange-chrom.pdf> as a PDF--cited herein), as evidenced by Zou et al (Zou et al., 2023, The AAPS Journal—cited herein), as evidenced by Biorad (Biorad, 2026, “Introduction to Multimodal or Mixed-Mode Chromatography,” downloaded 22 April 2026 from < https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG44> as a PDF—cited herein), and as evidenced by Korneyeva and Rosenthal, 2005, Methods in Molecular Biology—cited herein) in further view of Chen et al (Chen et al., 2018, WO 2018/039499 A9—cited herein).
The teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal are discussed above and incorporated into the instant rejection.
Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal do not teach that the amount of PLBD2 in the HIC eluate is reduced compared to amount of PLBD2 in the HIC load (claims 13 and 46) and the utilization of HIC media, Phenyl Sepharose™ High Performance (claim 26). Chen et al. teaches hydrophobic interaction chromatography as the most efficient at removing residual PLBD2 when purifying monoclonal antibodies (p. 73, Table 11, pargraph 00272). Chen et al. teaches the utilization of the hydrophobic interaction column, Phenyl Sepharose™ High Performance (paragraph 00274).
Therefore, it 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 combine the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and Chen et al. to utilize hydrophobic interaction chromatography to remove PLBD2 during Dupilumab manufacturing because host cell proteins and nucleic acid molecules that need to be eliminated from the final pharmaceutical grade product (paragraph 0002). One would be motivated to combine these teachings to arrive at the instant claims to utilize hydrophobic interaction chromatography to remove PLBD2 during Dupilumab manufacturing because any host cell proteins in the product may affect the overall quality or quantity or both (paragraph 0003). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and Chen et al. to utilize hydrophobic interaction chromatography to remove PLBD2, since Chen et al. teaches PLBD2 removal by hydrophobic interaction chromatography.
36. Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Keszey and Suto (Keszey and Suto, 2021, WO 2020200980 A1—cited on the IDS filed 27 September 2023), as evidenced by Thermo (Thermo, “Ion Exchange Chromatography,” downloaded 30 April 2026 from <https://documents.thermofisher.com/TFS-Assets/LSG/Application-Notes/TR0062-Ion-exchange-chrom.pdf> as a PDF--cited herein), as evidenced by Zou et al (Zou et al., 2023, The AAPS Journal—cited herein), as evidenced by Biorad (Biorad, 2026, “Introduction to Multimodal or Mixed-Mode Chromatography,” downloaded 22 April 2026 from < https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG44> as a PDF—cited herein), and as evidenced by Korneyeva and Rosenthal, 2005, Methods in Molecular Biology—cited herein) and in further view of cytiva II (cytiva II, 2020, “Capto Anion and Cation Exchange,” downloaded as a PDF from <https://www.cytivalifesciences.com/en/us/products/category/chromatography/prepacked-columns/ion-exchange> on 5 May 2026—cited herein).
The teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal are discussed above and incorporated into the instant rejection.
Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal do not teach the utilization of the anion exchange resin, Capto™ Q ImpRes (claim 21) and the utilization of the cation exchange resin, Capto™ SP ImpRes (claim 22).
Cytiva teaches Capto™ SP ImpRes and Capto™ Q ImpRes are strong cation and strong anion exchange BioProcess™ chromatography resins for the intermediate purification and polishing of a wide range of biomolecules (p. 1, lines 1-3).
Therefore, it 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 combine the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and cytiva II to utilize the Capto™ S P ImpRes and Capto™ Q ImpRes as strong cation and strong anion exchange resins to polish and purify Dupilumab because the resins are utilized for purification and polishing of a variety of biomolecules. One would be motivated to combine these teachings to arrive at the instant claims to utilize Capto™ SP ImpRes and Capto™ Q ImpRes resins because they offer flexibility of design, ease of optimization and scale up, higher manufacturing productivity, and comprehensive regulatory support (p. 1, bullets). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal and cytiva II to utilize the Capto™ S P ImpRes and Capto™ Q ImpRes as strong cation and strong anion exchange resins, since cytiva II teaches the utilization of these resins in polishing and purification steps of biomolecules.
37. Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Keszey and Suto (Keszey and Suto, 2021, WO 2020200980 A1—cited on the IDS filed 27 September 2023), as evidenced by Thermo (Thermo, “Ion Exchange Chromatography,” downloaded 30 April 2026 from <https://documents.thermofisher.com/TFS-Assets/LSG/Application-Notes/TR0062-Ion-exchange-chrom.pdf> as a PDF--cited herein), as evidenced by Zou et al (Zou et al., 2023, The AAPS Journal—cited herein), as evidenced by Biorad (Biorad, 2026, “Introduction to Multimodal or Mixed-Mode Chromatography,” downloaded 22 April 2026 from < https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG44> as a PDF—cited herein), and as evidenced by Korneyeva and Rosenthal, 2005, Methods in Molecular Biology—cited herein) and in further view of 3M Purification Inc (3M Purification Inc., 2012, “LifeAssure™ PNA Series Filters” downloaded 5 May 2026 from <https://multimedia.3m.com/mws/media/835216O/lifeassure-pna-series-bioburden-fine-particle-reduction-filters.pdf > as a PDF—cited herein).
The teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal are discussed above and incorporated into the instant rejection.
Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal do not teach the utilization of a LifeAssure™ filter after the viral inactivation step.
3M Purification Inc. teaches the utilization of LifeAssure™ filters for microorganism and fine particle control (p. 1, lines 4-5).
Therefore, it 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 combine the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal with 3M Purification Inc. to utilize a LIfeAssure™ filter after viral inactivation to reduce the presence of microorganisms. One would be motivated to combine these teachings to arrive at the instant claims to utilize a LifeAssure™ filter for rigorous contaminant control with long service life and low operating costs, as taught by 3M Purification Inc (paragraph 1, lines 8-10). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Keszey and Suto as evidenced by Thermo, as evidenced by Zou et al., as evidenced by Biorad, and as evidenced by Korneyeva and Rosenthal with 3M Purification Inc. to utilize a LIfeAssure™ filter after viral inactivation, since 3M Purification Inc. teaches its utilization in particle control and sterilization.
Double Patenting
38. 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
39. Claims 1-2, 17, and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 32 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 necessarily anticipate the instant claims.
The instant claims are drawn to a method comprising the steps of: (a) subjecting harvested Dupilumab (or anti-IL4Rα) 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; where claim 17 is drawn to an additional step of culturing cells expressing Dupilumab, subjecting said cells to transient pH levels from 4-5.5 and then raising the pH to 5.5-6.5, and then harvesting said cells by centrifugation, and finally undergoing steps a-f above.
The ‘354 claims in their broadest are drawn to a method for producing Dupilumab or anti-IL-4α, comprising: (a) culturing cells expressing dupilumab or anti-IL-4α using a cell culture medium comprising ornithine at between about 0.09 and 0.9mM and/or putrescine at between about 0.2-0.9mM; (b) harvesting said cell by centrifugation to separate cell debris from clarified media comprising Dupilumab or anti-IL-4α; (c) subjecting said clarified media to affinity chromatography; (d) subjecting said Dupilumab or anti-IL-4α pooled from eluate of step (c) to viral inactivation at a pH from about 3-4 and then adjusting the pH from about 5-8; (e) subjecting said Dupilumab or anti-IL-4α pooled from step (d) to anion exchange chromatography in flowthrough mode; (f) subjecting said Dupilumab or anti-IL-4α poled from flowthrough fractions of step (e) to cation exchange chromatography in bind and elute mode; (where steps (e) and (f) are reversed in claim 7); (g) subjecting said Dupilumab or anti-IL-4α pooled from eluate of step (f) to hydrophobic interaction chromatography in flowthrough mode (or not in claim 7); (h) subjecting said Dupilumab or anti-IL-4α pooled from flowthrough fractions of step (g) to virus retentive filtration to produce Dupilumab or anti-IL-4α, and (i) collecting said Dupilumab or anti-IL-4α.
The difference between the ‘354 claims and the instant claims in the inclusion of a cell culture and harvest step prior to the processing of the harvested Dupilumab; however the ‘354 claims would still necessarily anticipate the instant claims, since the methods claims in the instant application are written in “open language,” which would allow for the additional pre-harvest steps of cell culturing.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
40. Claims 1-3, 5-11, 14, 17-25, 29-32, 34-36, 38-43, 47, and 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 17-18, 21-24, 26-30, 33-43, 49-50, and 53 of copending Application No. 18/115,354 (reference application) as evidenced by Biorad (Biorad, 2026, “Introduction to Multimodal or Mixed-Mode Chromatography,” downloaded 22 April 2026 from < https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG https://www.bio-rad.com/en-us/applications-technologies/introduction-multimodal-or-mixed-mode-chromatography?ID=LUSN9AKG44> as a PDF—cited herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘914 claims would necessarily anticipate the instant claims.
The instant claims are drawn to a method comprising the steps of: (a) subjecting harvested Dupilumab (or anti-IL4Rα) 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; where claim 17 is drawn to an additional step of culturing cells expressing Dupilumab, subjecting said cells to transient pH levels from 4-5.5 and then raising the pH to 5.5-6.5, and then harvesting said cells by centrifugation, and finally undergoing steps a-f above
The ‘914 claims are drawn to a method comprising the steps of: (a) subjecting harvested Dupilumab (or anti-IL4Rα) 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 (where mixed-mode chromatography can be any mix of cation, anion, and/or hydrophobic interaction chromatography, as evidenced by BioRad, p. 4-5, bullet list) in flowthrough mode; (d) subjecting said Dupilumab pooled from flowthrough fractions of step (c) to anion exchange chromatography in bind and elute mode; and (e) subjecting said Dupilumab pooled from flowthrough fractions of step (d) to virus retentive filtration to produce Dupilumab; where claim 21 is drawn to an additional step of culturing cells expressing Dupilumab, subjecting said cells to transient pH levels from 4-5.5 and then raising the pH to 5.5-6.5, and then harvesting said cells by centrifugation, and finally undergoing steps a-e above.
The difference between the ‘914 claims and the instant claims is the inclusion of mixed-mode chromatography; however the ‘914 claims would still necessarily anticipate the instant claims, since the mixed mode chromatography step could include cation exchange, anion exchange, or a mix of both chromatography resins as evidenced by Biorad above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
41. Claims 1-3, 5-11, 14, 17-25, 29-36, 38-44, 47 and 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 14-22, 25-40, and 43 of copending Application No. 18/175,852 (reference application) in view of Kim et al (Kim et al., 2021, US 2021/0403580 A1—cited herein).
The instant claims are drawn to a method comprising the steps of: (a) subjecting harvested Dupilumab (or anti-IL4Rα) 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; where claim 17 is drawn to an additional step of culturing cells expressing Dupilumab, subjecting said cells to transient pH levels from 4-5.5 and then raising the pH to 5.5-6.5, and then harvesting said cells by centrifugation, and finally undergoing steps a-f above.
The ‘852 claims are drawn to a method comprising the steps of: (a) subjecting harvested Dupilumab (or anti-IL4Rα) 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 cation exchange chromatography in flowthrough mode; (d) subjecting said Dupilumab pooled from flowthrough fractions of step (c) to anion exchange chromatography in bind and elute mode; and (e) subjecting said Dupilumab pooled from flowthrough fractions of step (d) to virus retentive filtration to produce Dupilumab; where claim 21 is drawn to an additional step of culturing cells expressing Dupilumab, subjecting said cells to transient pH levels from 4-5.5 and then raising the pH to 5.5-6.5, and then harvesting said cells by centrifugation, and finally undergoing steps a-e above.
The ‘852 claims do not teach the hydrophobic interaction chromatography step of the instant claims. Kim et al. teaches the recovery of the antibody or antigen binding fragment thereof (anti-IL4R) by centrifugation or ultrafiltration to remove impurities and further purification of the resulting product using, for example, affinity purification of the resulting product using, for example, affinity chromatography, anion or cation exchange chromatography, hydrophobic interaction chromatography and hydroxyapatite chromatography (paragraph 0113).
Therefore, it 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 combine the teachings of Kim et al. with the claims of the ‘852 patent to produce Dupulimab. One would be motivated to combine these teachings to arrive at the instant claims to produce Dupulimab with an additional hydrophobic interaction chromatography step because this step would provide additional purification of the resulting produce as taught by Kim et al. There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Kim et al. with the ‘852 claims, since Kim et al. teaches the utilization of hydrophobic interaction chromatography in the purification of anti-IL4R.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
42. All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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/CIARA A MCKNIGHT/
Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
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