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 Claims
This office action is in response to the communication of 12/30/2022
Claims 1-10 are pending.
Claim Objections
Claim 7 is objected to because of the following informalities: there appears to be a typo in the scientific notation (“106” instead of 106 or 10^6). Appropriate correction is required.
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 1-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term "increasing" in claim 1 is a relative term which renders the claim indefinite. The term "increasing" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what the speed is increasing from, or increasing to, or even over what period of time this increase in speed is to take place. For the purposes of examination, this limitation will read on any increase in the rpm of a bioreactor at any point in time and to any degree no matter how small.
When reading the preamble in the context of the entire claim, the recitation “a method for preparing a bispecific antibody … comprising…” is not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations. Thus, the preamble of the claim(s) is not considered a limitation and is of no significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). For the purposes of examination, the limitation that the method is for preparing a bispecific antibody will be examined as part of the claimed method. A potential remedy for this rejection would be to include the bispecific antibody limitation in the body of the claim.
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.
For example, in claim 1, in addition to grammatical issues the claim simply doesn’t make sense as written. It is unclear based on the specification Claim 1 when the rotational speed of the bioreactor must fall between the claimed range, or for what period of time. Since the claim as written used the term “number of days” (plural) it is assumed that the claimed cell culture period is at least more than one day. Claim 1 is interpreted as if it appeared as:
“A method for preparing a bispecific antibody using an orbitally shaken bioreactor, the method comprising culturing cells in an orbitally shaken bioreactor for a cell culture period, wherein the cell culture period is for at least two days, wherein the orbitally shaken bioreactor has a rotational speed that increases at least once during the cell culture period, and wherein the rotational speed at any point during the cell culture period is in the range from 85 rpm to 110 rpm.”
For purposes of examination, the rotational speed either before or after the increase in speed may be between 85-110 rpm.
Claim 5 contains the trademark/trade names “Excel-Advanced” and “Feed 4”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe components of the cell culture media and, accordingly, the identification/description is indefinite.
Claims 2-10 are rejected for being dependent on an indefinite claim.
Claim Rejections - 35 USC § 103
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.
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.
Burgin and Fischer
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over:
Fischer (Fischer, Simon et al. “miRNA engineering of CHO cells facilitates production of difficult-to-express proteins and increases success in cell line development.” Biotechnology and bioengineering vol. 114,7 (2017): 1495-1510), and
Burgin (Bürgin, T. et al. (2020). Orbitally Shaken Single-Use Bioreactor for Animal Cell Cultivation: Fed-Batch and Perfusion Mode. In: Pörtner, R. (eds) Animal Cell Biotechnology. Methods in Molecular Biology, vol 2095. Humana, New York, NY.)
Regarding claim 1, Burgin teaches a protocol for preparing monoclonal antibodies in an SB10-X Bioreactor, which is an orbitally shaken bioreactor. (Burgin, section “3.4.1 Cell Cultivation in Fed-Batch Mode”). Burgin teaches that the cells are cultured inside the reactor, with a starting rotational speed of 85rpm. (Burgin, section “3.4.1 Cell Cultivation in Fed-Batch Mode”).
Regarding the limitation that the rotational speed increases at some point during the cell culture period (“has a rotational speed increasing at least once with the increase of number of days of culture”), Burgin teaches that when inoculating the bioreactor, certain parameters must be adjusted based on the working volume, including rpm (Burgin, Note 3, Note 6). For example, in a 10L working volume bioreactor, Burgin found that it was necessary to increase the shaking frequency during the cell growth phase from 100 to 110 rpm. (Burgin, Note 6) Thus, Burgin teaches that the practice of adjusting or increasing the rpm of a bioreactor while culturing cells is known in the art and was a routinely optimized parameter when culturing cells in an orbitally shaken bioreactor. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144(II)(A)).
Regarding the limitation that the claimed method is for preparing a bispecific antibody, Burgin generally teaches that their method may be used to produce monoclonal antibodies with CHO cells. Burgin selected CHO-K! recombinant cell line expressing Alemtuzumab as an “example protein”. (Burgin, section “3.4.1 Cell Cultivation in Fed-Batch Mode”, Section 2.2.1). Burgin does not appear to teach that their method could not be used for other types of antibodies. However, Burgin does not specifically mention that their method may be used to produce bispecific antibodies.
Fisher teaches the production of bispecific antibodies in an orbitally shaken bioreactor. Fischer teaches culturing cells at 37°C, 5% CO2 and with agitation at 125 rpm (50 mm orbit) in an orbital shaker incubator (Infors, Bottmingen, Switzerland). BI proprietary serum‐free, chemically‐defined, and animal component free cell culture media were used for cultivation. Seeding cell density of stock cultures was set to 0.3 × 106 viable cells per milliliter and cells were passaged in a 4/3-day rhythm. (Fischer, Materials and Methods, Cell Culture section). Fischer teaches the preparation of bispecific antibodies from a CHO cell line, as well as other non-bispecific antibodies from similar CHO cell lines, all in orbitally shaken bioreactors (Fischer Table I). So, Fisher teaches that production of bispecific and non bi-specific antibodies with CHO cells in an orbitally shaken bioreactor was known in the art. Burgin when producing monoclonal antibodies also using CHO cells teaches the claimed specific parameters of the claimed method.
Lastly, Burgin teaches certain benefits of using an orbitally shaken bioreactor (OSB) over other types such as a paddle agitated reactor. Burgin teaches that an OSB introduces less shear forces to the cell culture medium than other bioreactors that utilize impeller blades to stir the medium. (Burgin, Introduction 1.1).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to produce bi-specific antibodies in an OSB as taught by Fischer, in the bioreactor culture method taught by Burgin. One of ordinary skill in the art would have been motivated to do so, since Burgin teaches the claimed method and suggests that the method could be used to produce different antibodies, and Fischer provides a teaching, suggestion, and motivation to produce bispecific antibodies in a similar OSB.
One of ordinary skill in the art would have had a reasonable expectation of success, since Fischer teaches that bispecific antibodies may be successfully produced in an OSB.
Regarding claim 2 and 3, Burgin teaches that the temperature of cell culture decreases from 37 to 32°C four days after inoculation of the bioreactor. (Burgin, section “3.4.1 Cell Cultivation in Fed-Batch Mode”, step 5).
Regarding claim 4, the medium used in Burgin’s bioreactor of section “3.4.1 Cell Cultivation in Fed-Batch Mode” is described in section 2.2.1 CHO Cells for Fed-Batch Cultivation. Burgin’s CHO medium comprises Growth A basal medium containing 6 mM L-glutamine (Irvine Scientific) and supplemented with Pluronic (0.1 % V/V) and glucose (4 g/L). (Burgin, Section 2.2.1)
Regarding claim 5, Burgin’s CHO medium has a glucose concentration of 4g/L. (Burgin, Section 2.2.1)
Regarding claim 6, Burgin teaches that the culture medium in the bioreactor starts with a pH of 7.0 (Burgin, Section 3.4.1)
Regarding claim 7, The claimed range for cell seeding density is from 3x10^5 and 5x10^5 cells/mL. Burgin teaches that the initial seeding density is 2x10^5 cells/mL, which is outside of the claimed range. However, Burgin also notes that optimal seed densities need to be determined beforehand (Burgin, Note 20).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 8, Burgin’s method uses CHO-K1 recombinant cell line. (Burgin, Section 2.2.1, 3.4.1)
Regarding claim 9, Burgin’s CHO cells are genetically modified to express the example antibody. (Burgin, Section 2.2.1)
Burgin, Fischer, and Klein
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over:
Fischer (Fischer, Simon et al. “miRNA engineering of CHO cells facilitates production of difficult-to-express proteins and increases success in cell line development.” Biotechnology and bioengineering vol. 114,7 (2017): 1495-1510), and
Burgin (Bürgin, T. et al. (2020). Orbitally Shaken Single-Use Bioreactor for Animal Cell Cultivation: Fed-Batch and Perfusion Mode. In: Pörtner, R. (eds) Animal Cell Biotechnology. Methods in Molecular Biology, vol 2095. Humana, New York, NY.)
Klein (Klein, Christian, et al. "Engineering therapeutic bispecific antibodies using CrossMab technology." Methods 154 (2019): 21-31).
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Burgin and Fischer.
Regarding claim 10, Burgin and Fischer teach the method of claim 9, but fail to specify that the bispecific antibody is either an anti-CD3 x anti-CD20 or an anti-CD3 x anti-HER2 bi-specific antibody.
Klein teaches the production of an anti-CD3 x anti-CD20 bispecific antibody. Klein teaches that their CD3xCD20 antibody was in Phase I/1b clinical trials. (Klein Table 2, CD20-TCB antibody). Klein teaches that their antibodies may be produced using established up- and downstream manufacturing processes applied for classical IgG antibodies including CHO cell line expression, and that their bi-specific antibody is similar to IgG antibody production in terms of scale, yield, glycosylation, stability, and quality. (Klein, pg. 22, left column, first full paragraph.).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to produce Klein’s anti-CD3 x anti-CD20 bispecific antibody, with the bioreactor production method taught by Burgin and Fischer. One of ordinary skill in the art would have been motivated to do so, since this combination would be combining prior art elements according to known methods to yield predictable results. (MPEP 2143 (I)(A)). Burgin and Fisher teach the claimed method, which may be used to produce bispecific antibodies. Klein teaches the claimed bi-specific antibody, and even teaches that it may be produced by conventional scaleup methods, which would reasonably include bioreactors. Thus, the skilled artisan could have used Burgin and Fisher’s method to produce Klein’s antibody by a known method, yielding the predictable result of producing Klein’s antibody.
One of ordinary skill in the art would have had a reasonable expectation of success, since Burgin and Klein teach that their method may be used to generate bispecific antibodies.
Conclusion
Claims 1-10 are rejected. Claim 7 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THOMAS RUSSE AMICK whose telephone number is (571)272-5474. The examiner can normally be reached 7:30-5 M-F.
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/THOMAS R. AMICK/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638