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 1-39 and 44-45 are pending and subject to examination on the merits.
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.
Information Disclosure Statement
3. The information disclosure statements (IDS) submitted on 21 July 2026 have been considered by the examiner. See initialed and signed PTO/SB/08’s.
Withdrawn Objections/Rejections
4. The objection to the specification for the presence of embedded hyperlinks is withdrawn, since the specification was amended to delete them.
5. The objection to the specification for the presence of trademarks is withdrawn, since the trademarked names were properly denoted with the trademark symbol.
6. The objection to claim 1 for a comma instead of a semicolon at the conclusion of 1(a) is withdrawn, since the claim was amended to substitute the semicolon for the comma.
7. The objections to claims 13 and 38 for reciting “NaHCO3, Na2HPO4… CuSO4, ZnSO4, FeCl3, NiSO4, Na4 EDTA, and Na3 citrate EDTA” are withdrawn, since the claims were amended to recite “NaHCO3, Na2HPO4… CuSO4, ZnSO4, FeCl3, NiSO4, Na4 EDTA, and Na3 citrate EDTA.”
8. The objections to claims 19 and 31 for periods in the claims ate withdrawn, since the periods were omitted from the claims.
9. The objections to claims 30-31 for reciting VCD without first defining the term are withdrawn, since claim 29 defined the term (upon which both depend).
10. The 35 U.S.C. 112(b) indefiniteness rejection to claim 6 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
11. The 35 U.S.C. 112(b) indefiniteness rejection to claim 12 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
12. The 35 U.S.C. 112(b) indefiniteness rejection to claim 17 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
13. The 35 U.S.C. 112(b) indefiniteness rejection to claim 18 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
14. The 35 U.S.C. 112(b) indefiniteness rejection to claim 20 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
15. The 35 U.S.C. 112(b) indefiniteness rejection to claim 21 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
16. The 35 U.S.C. 112(b) indefiniteness rejection to claim 22 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
17. The 35 U.S.C. 112(b) indefiniteness rejection to claim 23 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
18. The 35 U.S.C. 112(b) indefiniteness rejection to claim 24 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
19. The 35 U.S.C. 112(b) indefiniteness rejection to claim 25 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
20. The 35 U.S.C. 112(b) indefiniteness rejection to claim 26 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
21. The 35 U.S.C. 112(b) indefiniteness rejection to claim 27 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
22. The 35 U.S.C. 112(b) indefiniteness rejection of claims 28-31 for reciting “improved bioreactor” is withdrawn, since the claim was amended to delete the term, “improved.”
23. The 35 U.S.C. 112(b) indefiniteness rejection to claim 29 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
24. The 35 U.S.C. 112(b) indefiniteness rejection to claim 30 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
25. The 35 U.S.C. 112(b) indefiniteness rejection to claim 31 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
26. The 35 U.S.C. 112(b) indefiniteness rejection to claim 37 for reciting “the step” is withdrawn, since the limitation was deleted from the claim.
New Rejection—necessitated by claim amendments
Claim Rejections - 35 USC § 112(b)
27. 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.
28. Claims 1-39 and 44-45 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or joint inventor regards as the invention. This is because the claims attempt to recite a process without setting forth any steps involved in the process. Specifically, claim 1(c) recites "using an affinity column,” claim 1(e) recites “using an anion exchange column,” claim 1(f) recites “using a cation exchange column,” claim 1(g) recites “using a HIC column,” claim 7(c) recites “using an affinity column,” claim 7(e) using an MMC column,” claim 32(b) recites “using an affinity column,” claim 32(e) recites “using an anion exchange column,” and claim 32(f) recites “using a cation exchange column.” Claims 2-6, 8-39, and 44-45 are included in the instant rejection. It is noted, the recitation of a "use" without any active, positive steps delimiting how the use is practiced is deemed indefinite. See MPEP 2173.05(q).
Claims 2-6, 8-39, and 44-45 are included in the instant rejection, since they do not mitigate the issue.
Modified/Maintained Rejections—necessitated by claim amendments
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, 32-39, and 44-45 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 previously), and Xenopoulos (Xenopoulos, 2017, US 9809799 B2—cited previously).
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”). Regarding claims 44-45, drawn to the cell culture medium being chemically defined medium, Johnson et al. teaches embodiments, where the medium is chemically defined (paragraph 0013).
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 previously) 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 previously). 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
33. 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.
34. 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.
35. 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.
36. 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.
37. 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.
38. 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.
Applicant’s Arguments and Examiner’s Rebuttal
The applicant disagrees with the obviousness rejection over Johnson et al., in view of Kim et al., and Xenopoulos et al. The applicant also disagrees with the obviousness rejection over Johnson et al., in view of Emmerson et al., as evidenced by ZETA.
First, the applicant argues that Johnson et al. teaches taurine-supplemented media and not the harvest pre-treatment, centrifugation, chromatography, viral inactivation, or virus retentive filtration. The examiner agrees insofar that Johnson et al. was not relied on for the teachings of these downstream processes. It was relied upon for the teaching of the medium constituents, where the medium of the instant claims is limited to “comprise” the listed constituents, which allows for the teachings of Johnson et al. to be applicable, although the medium also contains taurine.
Second, the applicant argues that Kim et al. does not teach the culturing methods in cell culture medium, followed by harvest pre-treatment, harvesting, affinity chromatography, viral inactivation, mixed-mode chromatography in flowthrough mode, and virus retentive filtration. The examiner agrees insofar that the Kim et al. teaching was not relied upon to teach all of these limitations. It was relied upon to teach the recovery of the antibody and following polishing steps.
Third, the applicant argues that there would be no motivation for a person with ordinary skill in the art to select these combinations of method steps out of the options disclosed in Kim et al. (i.e. further purification steps utilizing affinity purification or various other modes of chromatography). However, the examiner disagrees that a motivation is needed to combine these methods because 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).
Fourth, the applicant argues that Kim et al. merely lists generic descriptions of broad categories of chromatography may be used to purify an antibody, which does not amount to teaching the specifically claimed methods. The examiner respectfully disagrees because the claims also list the chromatographic techniques in the same broad terms, and Kim et al. teaches that any combination or all of these in addition to other steps may be used. Outside new or unexpected results, Kim et al. teaches all of the claimed techniques and the reordering and/or changing the steps is obvious.
Fifth, the applicant argues that Kim et al. does not teach the utilization of cell culture medium with ornithine and/or putrescine. The examiner agrees insofar that Kim et al. does not teach these limitations and was not used to meet these claim limitations. The teachings of Johnson et al. were utilized for these limitations.
Sixth, the applicant then argues again that the absence of motivation for selecting the combination of methods taught by Kim et al. is not the proper basis for an obviousness rejection. However, as stated above, the examiner respectfully disagrees and continues to argue that the selection of the various chromatographic steps needs a motivation and is simply a product of selecting the combination of taught chromatography methods, which is obvious absent any new and/or unexpected results with the specific ordering of the chromatography steps. Additionally, the applicant asserts that Kim et al. merely lists a laundry list of purification techniques; however, the examiner respectfully disagrees with this assessment because Kim et al. only lists five chromatography steps (p. 11, Remarks, paragraph 0113 of Kim et al., “…affinity chromatography. Other additional purification techniques such as anion or cation exchange chromatography, hydrophobic interaction chromatography and hydroxyapatite chromatography may be used.”), where instant claim 1 lists four.
Seventh, the applicant argues that there is no order listed by Kim et al. The examiner agrees insofar that Kim et al. does not list a specific order of the techniques. However, it is well-known in the art that affinity chromatography would be the first step of antibody purification, followed by any number of “polishing steps.” A polishing step would include any anion or cation chromatography, hydrophobic interaction chromatography, or multimodal/mixed mode chromatography (See Bjorkman, p. 2, “Typical techniques used for polishing”—cited herein).
Eighth, the applicant argues that Xenopoulos does not teach the claimed culture media or downstream processing steps. Again, the examiner did not use the Xenopoulos teachings for these limitaitons, it was utilized to teach viral inactivation by pH changes.
Nineth, the applicant argues that there would be no motivation to combine the teachings of Johnson et al., Kim et al., and Xenopoulos et al. However, the examiner respectfully disagrees because a motivation was given in the rejection above; specifically, “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)."
Tenth, the applicant argues that viral retentive filtration was not considered. However, Xenopoulos et al. 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)”—which is viral retentive filtration. The specification teaches that viral retentive filtration can be achieved by virus retentive membranes. It is the examiner’s position that matrices and membranes are equivalent.
Eleventh, the applicant argues that Johnson et al. does not teach or suggest a method including culturing cells expressing dupilumab in a large-scale bioreactor including one or more optical probes for measuring dissolved gases. Additionally, the applicant argues that Johnson et al. does not teach dupilumab production in a bioreactor with at least one on-line capacitance probe. The examiner agrees insofar that the examiner does not rely on Johnson et al. for these teachings but rather Emmerson et al. as evidenced by ZETA.
Twelfth, the applicant argues that Emmerson et al. does not expressly teach or suggest culturing cells expressing dupilumab in a large-scale bioreactor. The examiner agrees insofar that the teachings of Emmerson et al. was not utilized to teach this limitation.
Thirteenth, the applicant argues that Emmerson et al. is focused on bulk physical property measurement. The examiner agrees that Emmerson et al. teaches this technique in parallel. Emmerson et al. also teaches the specific measurement of properties, such as gas content. Specifically, Emmerson et al. teaches, “This [physical property] may be a property of a liquid content ( for example, its refractive index ), but could include measurements of gas in the head space, or other properties (such as dielectric properties and mass build - up ). The measurements are obtained in situ, and are passed by an electrical or optical cable” (paragraph 0044). Emmerson et al. does not opine that the measurements of gas in the headspace versus the bulk property measurements are better or worse; the differing measurements are merely alternatives. The MPEP states, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." (See 2143.01, Section I).
Fourteenth, the applicant argues that Emmerson et al. does not teach optical probes and only recites the use of “optical cables,” and does not correlate the type of cabling with the type of sensor. The examiner respectfully disagrees because Emmerson et al. teaches that a, “sensor comprises one or more transducer elements for transducing the changing physical parameter into a measurement signal , and a transmitting element for communicating the signal out of the reactor to a processor and control unit that processes the signal and determines the additive protocol therefrom. The transmitting element will likely be an electrical cable or an optical fibre (or bundle or ribbon of optical fibres), depending on the nature of the transducer element” (paragraph 0042). Therefore, it is the examiner’s position that the sensor must match the transducing cable, and additionally, the cables themselves are a part of the sensor. As a part of the sensor, optical cables would imply an optical sensor.
Fifteenth, the applicant disagrees that ZETA discloses a bioreactor with impellers and also does not teach producing dupilumab in a bioreactor with optical probes to measure dissolved gas and/or at least one on-line capacitance probe. ZETA discloses multiple bioreactors with impellers on p. 4, the top illustration. Additionally, ZETA is not utilized to teach producing dupilumab in a bioreactor with optical probes to measure dissolved gas and/or at least one on-line capacitance probe.
Sixteenth, the applicant disagrees that Emmerson et al. teaches sparging, i.e. adjusting CO2 and dissolved oxygen content. The applicant contends that Emmerson et al. does not teach a specific method or system to control the conditions of oxygen levels and/or CO2 levels. And further, the applicant argues that this is a generic sentence. The examiner respectfully disagrees. Emmerson et al. defines “the term " additive ” is used for any component, material or ingredient, gas, liquid or solid, which is added to the bioreactor during the bioreaction (paragraph 0040). And, paragraph 0044 does explicitly teach sparging, where fluid and/or solid feedstock and/or additives are injected into the bioreactor via tubing.
Seventeenth, the applicant argues that the methodology utilized by Emmerson et al. includes both on-line and off-line measurements taken together to then describe the VCC. The examiner agrees with this assessment. However, the examiner respectfully disagrees that this teaching does not reach the limitation of the instant claims of utilizing on-line measurements because the claim utilizes the “comprising” open language, which allows for additional steps not listed, i.e. off-line measurements.
Eighteenth, the applicant argues that Emmerson et al. does not teach culturing cells expressing dupilumab in a bioreactor with one or more optical probes Emmerson et al. was not utilized to reach these claim limitations. The applicant continues to argue that Emmerson is focused on yeast fermentation not mammalian cell culture. However, the examiner does not agree with this argument insofar that the examiner does not utilized Emmerson et al. to meet the limitations of the culture conditions but rather the real-time measurements and feedback loops associated with cellular growth in bioreactors. The applicant claims that this would result in hindsight reasoning. The examiner respectfully disagrees because bioreactors have been utilized widely for producing biological products, where nutrients are added to promote the growth of organisms of interest, as taught by Emmerson et al (paragraph 0002). Therefore, the well-known/described usage of bioreactors for differing organisms/cells does not make this combination a result of hindsight reasoning.
The examiner does not find the arguments presented by the applicant persuasive, and for these reasons, the rejections of record above apply.
Conclusion
39. All claims are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
40. 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
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