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 .
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.
Election/Restrictions
Applicant’s election of the species recited in subpart (a) of claim 24 in the reply filed on 12/22/25 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Information Disclosure Statement
Six information disclosure statements (IDS) were received on 3/16/22, 3/16/22, 3/16/22, 8/8/24, 4/23/25, respectively. All references have been considered. However, due to the voluminous number of references in the IDS, and the limited time available for review, the references have been only briefly considered. See also, Penn Yan Boats, Inc. v. Sea Lark Boats, Inc., 359 F. Supp. 948 (S.D. Fla. 1972) regarding applicant’s duty of disclosure.
Claim Status
Claims 1-5, 7, 9-11, 15-19, 21, 24-25 are currently pending and examined on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 7, 9-11, 15-21, 24-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims are generally narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors.
Generally, when the claims are indefinite, vague or unclear, they cannot be construed without speculation or conjecture; therefore, the indefinite claims are not treated on the merits with respect to prior art. See In re Steele, 305 F.2d 859, 862 (CCPA 1962) (A prior art rejection cannot be sustained if the hypothetical person of ordinary skill in the art would have to make speculative assumptions concerning the meaning of claim language.); see also In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970) ("If no reasonably definite meaning can be ascribed to certain terms in the claim, the subject matter does not become obvious-the claim becomes indefinite."). Notwithstanding Steele, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution. The following are exemplary of some of the issues present with the current claims, but may not comprise an exhaustive listing of all the issues present.
Claim 1 contains multiple instances of text contained in parentheses (e.g., “a concentration (viable cell density, VCD)”). It is unclear if the text present in the parentheses are required limitations of the claim or merely optional. For examination purposes, text contained within parentheses is not considered in the patentability analysis.
Claim 1 contains multiple limitations including the phrases “preferably”, “more preferably”, and “most preferably”. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following one of these phrases is not considered in the patentability analysis.
Claim 1 contains multiple limitations including the phrase “capable of” with respect to a structural element (e.g., “the permeate probe is capable to address the medium pump”). See Application of Collier, 397 F.2d 1003 (C.C.P.A. 1968), which states claims are considered indefinite when “things which may be done are not required to be done". Therefore, it is unclear if it a requirement that the recited structural elements actually perform the subsequently recited method steps.
Claim 1 recites the limitation "the perfusion rate" in the preamble. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the cells" in limitation (i). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the medium level" in limitation (ii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the bioreactor" in limitation (ii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the permeate rate" in limitation (ii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the medium pump" in limitation (ii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the medium feed rate" in limitation (ii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the medium probe" in limitation (ii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the outflow" in limitation (ii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the biomass" in limitation (iii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the bleed pump" in limitation (iii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the bleed rate" in limitation (iii). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 contains the limitation “providing an integrated first and the second control loop”. It is unclear what is intended by this limitation.
Claim 1 recites the limitation "the biomass value" in limitation (iv). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the equation" in limitation (iv). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the constant" in limitation (iv). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the permittivity" in limitation (iv). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the permittivity value" in limitation (iv). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the integration unit" in limitation (v). There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the measured biomass" in limitation (v). There is insufficient antecedent basis for this limitation in the claim.
Claim 2 contains multiple limitations including the phrase “preferably. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following ”preferably” is not considered in the patentability analysis.
Claim 5 contains the limitations “preferably” and “more preferably”. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following ”preferably” or “more preferably” is not considered in the patentability analysis.
Claim 7 contains the limitations including the phrases “preferably”, “more preferably”, and “most preferably”. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following one of these phrases is not considered in the patentability analysis.
Claim 9 contains the limitations “preferably” and “more preferably”. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following ”preferably” or “more preferably” is not considered in the patentability analysis.
Claim 10 contains the limitations including the phrases “preferably”, “more preferably”, and “most preferably”. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following one of these phrases is not considered in the patentability analysis.
Claim 11 contains the limitations including the phrases “preferably”, “more preferably”, and “most preferably”. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following one of these phrases is not considered in the patentability analysis.
Claim 15 contains multiple limitations including the phrase “preferably. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following ”preferably” is not considered in the patentability analysis.
Claim 16 contains the limitation “such as”. This phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, this limitation is not considered in the patentability analysis.
Claim 17 contains the limitation “preferably”. This phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, this limitation is not considered in the patentability analysis.
Claim 17 contains the limitation “i.e.”. This phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, this limitation is not considered in the patentability analysis.
Claim 18 contains the limitation “preferably”. This phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, this limitation is not considered in the patentability analysis.
Claim 19 contains multiple limitations including the phrase “preferably. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following ”preferably” is not considered in the patentability analysis.
Claim 21 contains the limitation “preferably”. This phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, this limitation is not considered in the patentability analysis.
Claim 25 contains the limitations including the phrases “preferably”, and “most preferably”. These phrases render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, any limitation following one of these phrases is not considered in the patentability analysis.
Claim 25 recites the limitation "the defined cell-specific perfusion rate. There is insufficient antecedent basis for this limitation in the claim.
Claim 25 recites the limitation "the biomass set-point". There is insufficient antecedent basis for this limitation in the claim.
Claim 25 contains the limitation “by feeding”. It is unclear what is being fed to the bioreactor (e.g., cells, media, etc.)
Claim Interpretation
In view of the above rejections, for examination purposes, claim 1 is interpreted as:
1. A manufacturing process comprising the steps of:
(i) providing a liquid cell culture medium comprising at least one mammalian cell culture in a perfusion bioreactor,
wherein the mammalian cell culture expresses an antibody product, and
wherein the cells have a viable cell density (VCD) of at least 1 x 105 cells/mL at inoculation;
(ii) providing a first control loop comprising:
(a) a level probe,
(b) a permeate pump, and
(c) a level control means,
wherein the level control means receives an input from the level probe and an input from the permeate pump,
wherein the level control means regulates a medium feed rate to the perfusion bioreactor via a medium pump in response to the input from the level probe and the input from the permeate pump, and
whereby a medium level in the perfusion bioreactor is measured at preset fixed time intervals of up to 1 minute;
(iii) providing a second control loop comprising:
(a) a permittivity probe or a Raman probe, the permittivity probe or the Raman probe positioned in the perfusion bioreactor, and
(b) a biomass control means,
wherein the biomass control means receives an input from the permittivity probe or the Raman probe,
wherein the biomass control means regulates a bleed rate of the perfusion bioreactor via a bleed pump in response to the input from the permittivity probe or the Raman probe;
wherein the measuring of the biomass in the bioreactor takes place at preset fixed time intervals;
(iv) integrating the first control loop and the second control loop by operably connecting the biomass control means and the level control means to an integration unit,
wherein the integration unit performs automated perfusion rate calculations; and
(v) automatically amending or maintaining the perfusion rate via the integration unit,
whereby the integration unit sends a signal to the permeate pump and/or the medium pump to increase or reduce a pump rate of the permeate pump and/or a pump rate of the medium pump.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-5, 7, 15, 25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Angelini et al., US Publication No. 2019/0153381 (hereinafter Angelini).
Regarding claims 1-3, 7, Angelini discloses methods of controlling a bioreactor system for the cell-based production of proteins, such as antibodies (Abstract, [0005], [0049]). Angelini discloses that the bioreactor system may include a tank, a feed reservoir, a feed pump (media pump), a bleed pump, a harvest pump, ATF pump (permeate pump), a bleed tank, and a harvest tank ([0068]). Each of the pumps may be operably coupled to a control system ([0068]). Angelini discloses that various components and instruments may be present within the bioreactor, including a Raman probe ([0071], [0074]-[0075]). Angelini explains that Raman probes may be used to provide real-time assessments of multiple process variables ([0075]). Process parameters that may be monitored include initial cell density, viable cell count, nutrient concentration, protein attributes, weight of the bioreactor, ammonia, pH, lactate, etc. ([0007], [0066]). Angelini discloses monitoring the working volume (i.e., volume within the bioreactor) by monitoring the weight of the bioreactor ([0099]-[0100]). Measuring of the process parameters within the bioreactor may occur at regular intervals, including at every 1 minute or less ([0008], [0106]). The control system may be configured to receive data from the Raman probe and other sensors ([0081]). The control system may automatically control the rate of fluid flow through one or more of the pumps based on the received data within certain predetermined set points ([0018], [0081]-[0086]). In some embodiments, the system may include two or more control loops run by an integrated controller ([0083], [0087]-[0088], [0094], Fig. 2). Angelini discloses that the controller may utilize various algorithms to monitor and assess process parameters ([0090]-[0091]).
Angelini discloses that any suitable eukaryotic cell, including mammalian cells may be utilized ([0050]). In particular Chinese hamster ovary (CHO) cells may be cultured to produce and antibody of interest ([0049], [0052]). In some embodiments, the cells may be present at a viable cell concentration (VCC) of each of 10 x106, 40 x106 , 42.5 x106, and 70 x106 cells/mL throughout the culture ([0115], [0122], a set VCC maintained throughout the culture is interpreted as initiating the cell culture at said density).
Regarding claim 2, Angelini discloses that the system may operate as a batch, fed-batch, or continuous perfusion culture process ([0046]-[0048], [0054]).
Regarding claim 4, Angelini discloses that the cells may be present in the culture at viable cell density (VCD) of at least 30 x106 cells/mL ([0082]).
Regarding claims 5, 15, 25, in some embodiments, the culture process may run for at least about 30 days ([0008]).
Therefore every limitation of claims 1-5, 7, 15, and 25 is present in Angelini, and the subject matter is anticipated.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 16-19, 21, 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Angelini as applied to claims 1-5, 7, 15, and 25 above, and further in view of Hansen et. Al. US Publication No. 2005/0070693 (hereinafter Hansen).
Angelini does not disclose that the antibody may have certain characteristics, comprise certain moieties, or comprise certain binding domains.
Hansen discloses methods of making anti-CD19 antibodies, anti-CD19 antibody fusion proteins and fragments thereof (Abstract). Hansen explains that anti-CD19 antibodies are highly useful for the treatment of multiple diseases and conditions ([0003], [0058], [0143]-[0144]). Hansen discloses that the antibodies may be produced by any suitable host cell, in particular CHO cells ([0078]).
Regarding claims 17, 19, Hansen discloses that the antibody may be a bispecific antibody which binds simultaneously to two targets of different structure ([0079]-[0081]).
Regarding claim 24, Hansen discloses that in some embodiments the CDRs of a light chain variable region of the monoclonal antibody comprises CDR1 comprising amino acids KASQSVDYDGDSYLN (corresponding to SEQ ID NO:1), CDR2 comprising amino acids DASNLVS (corresponding to SEQ ID NO:2), and CDR3 comprising amino acids QQSTEDPWT (corresponding to SEQ ID NO:3) (claims 8, 14). The CDRs of the heavy chain variable region of the monoclonal antibody comprises CDR1 comprising amino acids SYWMN (corresponding to SEQ ID NO:4), CDR2 comprising amino acids QIWPGDGDTNYNGKFKG (corresponding to SEQ ID NO:5), and CDR3 comprising amino acids RETTTVGRYYYAMDY (corresponding to SEQ ID NO:6) (claims 8, 14).
Regarding claim 21, Hansen does not explicitly disclose that the bispecific antibody includes a half-life extending moiety. However, Hansen discloses that the antibody may include modified Fc regions for improved effector functions, such as improved internalization capacity, complement fixation, etc. ([0042], [0058], [0069]). Therefore, there is a suggestion present in Hansen that Fc regions may be modified to improve the effect of the antibody such as by extending half-life.
As both Angelini and Hansen are directed to cell-based methods of making proteins, such as antibodies, it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would be motivated to make the antibodies of Hansen using the methods of Angelini for the easy, mass production of therapeutically important antibodies.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA D JOHNSON whose telephone number is (571)270-1414. The examiner can normally be reached Monday-Friday 8:00-4:00 CT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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