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 1-43 are pending and subject to examination on the merits. Claims 40-43 are withdrawn from consideration as being drawn to non-elected subject matter. Claims 1-39 are currently under examination.
Election/Restrictions
2. Claims 40-43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim.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.
Priority
3. 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.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted on 16 October 2023 and 05 January 2026 have been considered by the examiner. See initialed and signed PTO/SB/08’s.
Specification
5. 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.
6. The use of the term Allegra™ X-22 (paragraph 0495), Allegra™ 6R (paragraph 0501), MabCapture™ A (paragraph 0501), 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 where 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
7. Claim 1 is objected for the following informalities: “,” should be amended to “;” to conform with the punctuation throughout the rest of the claim and application. Appropriate corrections are required.
8. Claims 13 and 38 are objected for reciting “NaHCO3, Na2HPO4… CuSO4, ZnSO4, FeCl3, NiSO4, Na4 EDTA, and Na3 citrate EDTA.” It should be amended to “NaHCO3, Na2HPO4… CuSO4, ZnSO4, FeCl3, NiSO4, Na4 EDTA, and Na3 citrate EDTA” to conform with proper scientific notation of chemical names.
9. Claims 19 and 31 are objected to because of the following informalities: periods in claims (pCO.sub.2 and 2.5x10.sup.5) are not permitted except at the end of the claim and when used for abbreviations (See MPEP 608.01(m)). – see MPEP 2422.01 and 37 C.F.R. 1821(c) and (d). These should be changed the pCO2 and 2.5x105.
Appropriate corrections are required.
10. Claims 30-31 are objected for utilizing the abbreviation “VCD” without first defining said term. VCD should be first defined as “viable cell density,” this could be done by adding “(VCD)” after “viable cell density” in claim 29, line 3.
Claim Rejections - 35 USC § 112(b)
11. Claims 6, 12, 17-18, 20-31, and 37 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.
12. Claim 6 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
13. Claim 12 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
14. Claim 17 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
15. Claim 18 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
16. Claim 20 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
17. Claim 21 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
18. Claim 22 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
19. Claim 23 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
20. Claim 24 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
21. Claim 25 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
22. Claim 26 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
23. Claim 27 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
24. Claims 28-31 are indefinite for reciting the limitation “improved bioreactor.” There is no definition of “improved bioreactor” in the specification. Therefore, it is unclear how the bioreactor is improved or to what the improvement is compared, i.e. improved compared to what? For examination purposes, “improved bioreactor” will be interpreted as a bioreactor with any sort of additional feature, i.e. optical probes, ability to measure capacitance, any real time measurement ability such as pH, dissolved gasses, etc. Claims 29-31 are included in the instant rejection, since they do not mitigate the issue.
25. Claim 29 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
26. Claim 30 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
27. Claim 31 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
28. Claim 37 recites the limitation "the step" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 103
29. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-14 and 32-39 are rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al (Johnson et al., 2017, WO 2017/024062 A1—cited on the IDS dated 16 October 2023) and Kim et al (Kim et al., 2021, US 2021/0403580 A1—cited herein), and Xenopoulos (Xenopoulos, 2017, US 9809799 B2—cited herein).
Regarding claims 1, 7, and 32 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, Johnson et al. teaches the medium and methods thereof for culturing of recombinant eukaryotic cells for the production of protein biotherapeutics (paragraph 0001), where specifically, the protein biotherapeutic can be an antibody, Dupilumab (paragraph 00105), wherein the medium contains approximately 0.1 to 1mM ornithine (paragraph 00064), and further, wherein the medium contains putrescine from 0.1-1mM (paragraph 0065). Regarding claims 2-3, 8, and 33-34 drawn to the culture medium comprising one or more fatty acids, such as linoleic acid, linolenic acid, thioctic acid, oleic acid, palmitic acid, stearic acid, arachidic acid, arachidonic acid, lauric acid, behenic acid, decanoic acid, dodecanoic acid, hexanoic acid, lignoceric acid, myristic acid, octanoic acid, and combinations thereof, Johnson et al. teaches the addition of one or more fatty acids to the cell culture medium, wherein one or more fatty acids are selected from the group consisting of linoleic acid, thioctic acid, oleic acid, palmitic acid, stearic acid, arachidic acid, arachidonic acid, lauric acid, behenic acid, decanoic acid, dodecanoic acid, hexanoic acid, lignoceric acid, myristic acid, and octanoic acid (claims 52-53). Regarding claim 4, 9, and 35 drawn to the culture medium comprising nucleosides selected from the group consisting of adenosine, guanosine, cytidine, uridine, thymidine, hypoxanthine, and combinations thereof, Johnson et al. teaches a CHO cell medium comprising a mixture of nucleosides comprising one or more of adenosine, guanosine, cytidine, uridine, thymidine, and hypoxanthine (claims 55-56). Regarding claim 5, 11 and 36, drawn to the culture medium comprising amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and combinations thereof, Johnson et al. teaches the fed-batch medium and/or feed further comprising a mixture of amino acids selected from the group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan (claim 64). Regarding claims 6, 12-13, 10, and 37-38 drawn to further additions of point-of-use additions to the medium, such as insulin (claim 10), or one or more of point-of-use additions comprising one or more of NaHCO3, Na2HPO4, taurine, glutamine, poloxamer 188, insulin, glucose, CuSO4, ZnSO4, FeCl3, NiSO4, Na4 EDTA, Na3 citrate EDTA, Johnson et al. teaches adding one or more point-of-use additions to the cell culture medium, where the point-of -use addition is any one or more of NaHCO3, glutamine, insulin, glucose, CuSO4, ZnSO4, FeCl3, NiSO4, Na4EDTA, and Na3 Citrate (paragraph 0026). Regarding claim 14 and 39, drawn to the culture medium as hydrolysate-free, Johnson et al. teaches the cell culture medium is hydrolysate free (paragraph 0059, “MEDIA”).
Johnson et al. does not teach centrifugation to separate cell debris from clarified media comprising Dupilumab, subjecting said clarified media to affinity chromatography, subjecting said Dupilumab pooled from eluate to viral inactivation at pH from about 3-4 and then adjusting the pH to about 5-8, subjecting said Dupilumab pooled from eluate to anion exchange chromatography and then cation exchange chromatography (or in reverse, i.e. cation then anion exchange chromatography), subjecting said Dupilumab polled from the eluate to hydrophobic interaction chromatography in flowthrough mode, subjecting said Dupilumab pooled from flowthrough fractions to virus retentive filtration to produce Dupilumab and collecting said Dupilumab. 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). 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).
Johnson et al. and Kim et al. do not teach viral inactivation at a pH from about 3-4, adjusting the pH to about 5-8 and virus retentive filtration. Xenopoulos teaches the inactivation viruses during protein purification (abstract). Further, Xenopoulos teaches that virus inactivation is usually performed following elution from a bind and elute chromatography process step (e.g. Protein A affinity chromatography or cation exchange chromatography) because the pH of the elution pool is closer to the desirable pH for virus inactivation. For example, in processes used in the industry today, the Protein A chromatography elution pool typically has a pH in the 3.5-4.0 range and cation exchange bind and elute chromatography elution pool typically has a pH about 5.0 (Column 4, lines 17-26). Xenopoulos continues to teach that the sample (i.e. the elution pool) has to be transferred to a proper pool tank with mixing capabilities. The pH is then adjusted to desirable value, followed by one to two hours of incubation or longer, at the desirable pH value. Following mixing, the pH has to again be adjusted to the pH which is suitable for the next process step, which is usually a higher pH than for virus inactivation (Column 6, lines 30-44); specifically, the viral inactivation pH is adjusted to pH 3.3 to 3.6 (Column 24, Lines 33-39, Table III). The pH is then readjusted back up to pH 8 for the next purification step (Column 22, lines 19-21). Last, Xenopoulos teaches the utilization of two or more matrices selected from activated carbon, anion exchange media, cation exchange media, and virus filtration media (column 2, lines 59-65).
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 Johnson et al., Kim et al., and Xenopoulos to devise a method for producing Dupilumab by culturing cells expressing Dupilumab in medium with ornithine and/or putrescine, harvesting said cells by centrifugation, subjecting clarified media to affinity chromatography, subjecting said pooled Dupilumab from the eluate to viral inactivation, subjecting said Dupilumab to cation exchange chromatography, subjecting the eluate then to cation exchange chromatography, subjecting the eluate then to hydrophobic interaction chromatography, and finally subjecting said Dupilumab to virus retentive filtration and collection to increase productivity to significantly increase supply at the commercial scale of a biotherapeutic product as taught by Kim et al (paragraph 0006). One would be motivated to combine these teachings to arrive at the instant claims to devise a method to produce a recombinant protein, while minimizing the output of potentially toxic cell metabolism byproducts, such as ammonia, are highly desirable to support healthy and robust cell growth and maintenance to support the high-titer production of biopharmaceuticals as taught by Kim et al (paragraph 0007). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Johnson et al., Kim et al., and Xenopoulos, since Johnson et al. teaches the culture conditions necessary to produce the antibody and Kim et al. teaches the collection thereof.
32. Claims 15-29 are rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al (Johnson et al., 2017, WO 2017/024062 A1—cited on the IDS dated 16 October 2023) and Emmerson et al (Emmerson et al., 2017, US 2017 0253848 A1—cited herein) as evidenced by ZETA (ZETA, 2025, downloaded as a PDF on 22 April 2026 from < https://hsus.zeta.com/us-biotech-engineering?utm_campaign=21811333-US-BA&utm_source=bingads&utm_medium=cpc&utm_term=Bioprocessing%20equipment%20for%20biopharma&utm_campaign=US+Bioprocessing+%26+Engineering&utm_source=bing&utm_medium=ppc&hsa_acc=8410811225&hsa_cam=22982541359&hsa_grp=1185275485746124&hsa_ad=&hsa_src=o&hsa_tgt=kwd-74080161436549:loc-4123&hsa_kw=Bioprocessing%20equipment%20for%20biopharma&hsa_mt=p&hsa_net=bingads&hsa_ver=3&msclkid=f419cc992a9a105c59a2a57026b2ab17> --cited herein). Regarding claims 15 and 28, drawn to a method of producing Dupilumab, comprising the steps of (a) culturing cells expressing Dupilumab in a large-scale or improved bioreactor, wherein said bioreactor includes one or more optical probes for measuring dissolved gases (claim 15) or said improved bioreactor includes at least one on-line capacitance probe (claim 28); (b) culturing said cells in a culture medium comprising ornithine at between about 0.9-0.9 mM and/or putrescine at between about 0.2-0.9 mM (claim 15) or culturing said cells in a culture medium comprising one or more polyamines (claim 28), and (c) producing Dupilumab, Johnson et al. teaches the medium and methods thereof for culturing of recombinant eukaryotic cells for the production of protein biotherapeutics (paragraph 0001), where specifically, the protein biotherapeutic can be an antibody, Dupilumab (paragraph 00105), wherein the medium contains approximately 0.1 to 1mM ornithine (paragraph 0064), and further, wherein the medium contains putrescine (polyamine) from 0.1-1mM (paragraph 0065). Johnson et al. continues to teach that the cells cultured to produce Dupilumab is done so in a large-scale bioreactor (paragraph 00115, Example 1B—Benchtop-Scale Bioreactors). Regarding claims 18-19, drawn to adjusting the dissolved oxygen levels and/or pCO2 levels by sparging, Johnson et al. teaches an air sparge step of the bioreactor of 22 ccm for 14 days (paragraph 00115). Regarding claim 20, drawn to the method further comprising an addition of taurine or hypotaurine to the culture medium, Johnson et al. teaches the addition of about 1-10 mM taurine supplemented to the medium (paragraph 0010). Regarding claim 21, drawn to the addition of recombinant growth factors to the medium, Johnson et al. teaches that the solution may also contain components that enhance growth and/or survival above minimal rate, including hormones and growth factors (paragraph 0050). Regarding claim 22, drawn to the addition of one or more of adenosine, guanosine, cytidine, uridine, thymidine, and hypoxanthine, Johnson et al. teaches that the media contains adenosine, guanosine, cytidine, uridine, thymidine, and hypoxanthine (paragraph 0069). Regarding claim 23, drawn to the method further comprising adding fatty acids comprising one or more of linoleic acid, linolenic acid, thioctic acid, oleic acid, palmitic acid, stearic acid, arachidic acid, arachidonic acid, lauric acid, behenic acid, decanoic acid, dodecanoic acid, hexanoic acid, lignoceric acid, myristic acid, and octanoic acid, Johnson et al. teaches the medium supplemented with micromolar amounts of fatty acids, including one or more of linoleic acid, linolenic acid, thioctic acid, oleic acid, palmitic acid, stearic acid, arachidic acid, arachidonic acid, lauric acid, behenic acid, decanoic acid, dodecanoic acid, hexanoic acid, lignoceric acid, myristic acid, and octanoic acid (paragraph 0070). Regarding claim 24, drawn to an additional step of adding one or more salts selected from the group of divalent cations, such as calcium, magnesium, and a combination thereof, Johnson et al. teaches the addition of one or more osmolytes selected from a magnesium salt and/or a calcium salt among others (paragraph 0076). Regarding claims 25-26, drawn to the addition of amino acids having a non-polar side chain and basic amino acids, Johnson et al. teaches the addition of alanine, valine, isoleucine, leucine, methionine, phenylalanine, proline, glycine, and tryptophan; additionally, Johnson et al. teaches arginine, histidine, and lysine (claim 45). Regarding claim 27, drawn to the addition of nucleosides, salts of divalent cations, tocopherol, and vitamins, Johnson et al. teaches the CHO cell culture medium comprising a mixture of nucleosides (claim 55), a mixture of salts, including divalent cations, such as calcium and magnesium, specifically calcium chloride and magnesium sulfate (paragraph 0017), tocopherol (paragraph 0015), and vitamins (paragraph 0061).
Johnson et al. does not teach the utilization of optical probes for the measurement of dissolved gas (claim 15), wherein said dissolved gas is dissolved oxygen (claim 16), the agitation of said culture medium with one or more impeller assemblies, wherein an uppermost impeller is position below the surface of the initial working volume of the bioreactor (claim 17), adjusting the dissolved oxygen (claim 18) or pCO2 (claim 19) levels by sparging, a bioreactor including at least one on-line capacitance probe (claim 28), or applying an electric field to the cells in the bioreactor to measure capacitance and correlate said capacitance to viable cell density (VCD) (claim 29).
Regarding the utilization of optical probes for the measurement of dissolved gas (claim 15) and wherein said gas is dissolved oxygen (claim 16), adjusting said oxygen gas (claim 18) or pCO2 (claim 19), Emmerson et al. teaches systems and methods for automatic control of processes within bioreactors (paragraph 0001). Specifically, Emmerson et al. teaches the measurement of the bulk physical property of the bioreactor, including refractive index, gas in the head space, dielectric properties and mass build-up, where said measurements are obtained in situ and passed by an electrical or optical cable to the controller (paragraph 0044; Fig. 1). Emmerson et al. continues to teach a probing control operating in a system in which oxygen uptake is measured as an indicator of cellular activity (paragraph 0008), where a feedback loop may be established to control level, stirring, and carbon dioxide level (paragraph 0046). Regarding the impeller placements, Emmerson et al. does not teach a particular bioreactor but just a bioreactor outfitted with sensors; Zeta evidences a bioreactor schematic that shows multiple impellers within the bioreactor and the uppermost in the working volume of the bioreactor (See p. 4; schematic at top). Regarding adjusting CO2 and dissolved oxygen levels by sparging, Emmerson et al. teaches the measurement and feedback of maintaining CO2 and dissolved oxygen concentrations (paragraph 0046), where specifically oxygen can be fed into the bioreactor (paragraph 0008). Regarding adding an electric field and subsequent measurement of capacitance to calculate a viable cell density, Emmerson et al. teaches the on-line or off-line measurement of capacitance and the subsequent correlation to cell viability to infer a viable cell count (VCC) (paragraph 0006).
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 Johnson et al., Emmerson et al. as evidenced by ZETA to culture cells in a bioreactor and measure optical densities and capacitance to monitor growth in culture medium supplemented with polyamines, such as hypotaurine, to subsequently produce dupilumab because bioreactors are widely used in the production of biological products, such as monoclonal antibodies, e.g. dupilumab as taught by Emmerson et al (paragraph 0002) and Johnson et al (paragraph 0115). One would be motivated to combine these teachings to arrive at the instant claims to culture cells in a defined medium in a bioreactor to produce dupilumab because consistent gains in productivity can equate to significantly higher supply at commercial scale of a biotherapeutic product as taught by Johnson et al (paragraph 0006). There would be a reasonable expectation of success, yielding no surprising results when combining the teachings of Johnson et al. and Emmerson et al. as evidenced by ZETA to devise a method of culturing cells in a bioreactor with a defined medium in a bioreactor to produce dupilumab, since Johnson et al. teaches the utilization of a large-scale bioreactor to produce dupilumab.
Double Patenting
31. 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.
32. Claims 1, 7, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, and 34 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 necessarily anticipate the instant claims.
The instant 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 ‘809 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 difference between the ‘809 claims and the instant claims is the inclusion of the pH transitions before the harvest by centrifugation; however the ‘809 claims would still necessarily anticipate the instant claims, since the method claims in the instant application are written in “open language,” which would allow for this additional step in pH changing before harvesting the cells by centrifugation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
33. Claims 1, 7, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 21, and 33 of copending Application No. 18/175,914 (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 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 ‘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 the pH transitions before the harvest by centrifugation and the inclusion of mixed-mode chromatography; however the ‘914 claims would still necessarily anticipate the instant claims, since the method claims in the instant application are written in “open language,” which would allow for this additional step in pH changing before harvesting the cells by centrifugation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
34. Claims 15, 17-18, and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24, 26-27, 30, and 33 of copending Application No. 18/115,285 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘285 claims would necessarily anticipate the instant claims.
The instant claims in the broadest are drawn to A method of producing Dupilumab, comprising the steps of: (a) culturing cells expressing Dupilumab in a large-scale bioreactor, wherein said bioreactor includes one or more optical probes for measuring dissolved gases or an on-line capacitance probe; (b) culturing said cells in a 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; and (c) producing Dupilumab, wherein the step of agitating said culture medium with one or more impeller assemblies, wherein an uppermost impeller is positioned below the surface of an initial working volume of said bioreactor, wherein the step of adjusting dissolved oxygen levels by sparging said culture medium.
The ‘285 claims are drawn to a method for producing an anti-IL4Rα antibody, comprising the steps of: (a) culturing cells expressing an anti-IL4Rα antibody in a cell culture medium, wherein a cumulative concentration of one or more polyamines is between about .03 and 0.9 mM; (b) agitating said cell culture, and (c) controlling dissolved gas concentrations in said cell culture, wherein two or more impeller assemblies are positioned below a surface of initial working volume, wherein the uppermost impeller is below said initial working volume, and the dissolved gas concentrations (oxygen). are controlled by one or more spargers automatically.
The difference between the ‘285 claims and the instant claims is that the ‘285 claims do not recite Dupilumab directly; however, Dupilumab does target IL4Rα and is thus an anti-ILF4Rα antibody. Additionally, the ‘285 claims recite an agitation step. This would still anticipate the instant claims, since the instant claims use the open language “comprising” and thus can include an additional agitation step.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
35. Claims 1, 7, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 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 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 ‘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.
36. Claims 28-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, and 12 of copending application 18/115,321. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘321 claims would necessarily anticipate the instant claims.
The instant claims are drawn to a method of producing Dupilumab in an improved bioreactor, comprising the steps of: (a) culturing cells expressing Dupilumab in a vessel or bioreactor, wherein said bioreactor includes at least one on-line capacitance probe; (b) culturing said cells in a culture medium comprising one or more polyamines; and (c) producing Dupilumab, wherein further steps comprising i) applying an electric field to said cells cultured in a bioreactor; ii) measuring capacitance; and iii) correlating capacitance to viable cell density are added to the said method, transferring said cells when a final VCD reaches a target cell density, and lastly, comprising adjusting an initial VCD of a seed train to be at least 2.5x105 cells/mL.
The ‘321 claims are drawn to a method of producing Dupilumab, comprising culturing cells in a seed train, wherein said seed train includes cell cultures in N-5 to N-1 vessels or bioreactors, wherein the initial VCD is adjusted between 3.5 x105 to 5.43x105 cells/mL in each vessel or bioreactor, wherein the method comprises a) using at least one on-line capacitance probe to measure a first capacitance value of a first cell culture; b) using at least one off-line assay to measure a first viable cell density value of the said first cell culture; c) correlating said first capacitance value with the said first viable cell density value to determine a correlation equation; d) using an on-line capacitance probe to determine a second capacitance value of a second cell culture) using said second capacitance value and said correlation equation to predict at least one second viable cell density value of said second cell culture; and f) adjusting a working volume or viable cell density (VCD) based on said second viable cell density value to culture the cell, and wherein, a finally a method of producing Dupilumab comprising the steps of:(a) culturing cells wherein an initial viable cell density (VCD) in a seed train in vessels or bioreactors is adjusted to at least 2.5 x105 cells/mL; (b) measuring viable cell density by (i) applying an electric field to said cells cultured in a vessel or bioreactor; and (ii) measuring capacitance; and (iii) correlating capacitance to viable cell density; (c) adjusting initial VCD in each seed train vessel or bioreactor; and (d) producing Dupilumab.
The difference between the ‘321 claims and the instant claims is that the ‘321 claims explicitily state a second capacitance reading taken during the process of producing Dupilumab. This is implied in the instant claims, since the instant claims recite an initial and final VCD. Therefore, the ‘321 claims would necessarily anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
37. All claims are rejected.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
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