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 .
DETAILED OFFICE ACTION
This Office Action is in response to the claims filed on 16 September 2025.
PRIORITY
Foreign Priority Document EP18162761.3, filed on 20 March 2018, is acknowledged. The priority document does not provide support for the limitation “without inducing apoptosis as measured using a flow cytometer to identify Annexin V on day 5 of cell growth”. The earliest support for this limitation is the claims filed on 16 September 2025.
CLAIMS UNDER EXAMINATION
Claims 8-12, 14 and 17-21 are pending and have been examined on their merits.
WITHDRAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment.
NEW REJECTIONS
New rejections have been necessitated by claim amendment.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 8-12, 14 and 17-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 8 and 10 have been amended to recite the producer culture media increases product titer “without inducing apoptosis as measured using a flow cytometer to identify Annexin V on day 5 of cell growth”. The Applicant points to [0078] and [0080] of the specification. Examiner notes this is the PG Pub, not the original specification filed on 20 March 2019.
The originally filed specification discloses the following:
In the case of exponential phase addition, 2TAA at 2 mM produced a titer improvement of 3.2-fold over the vehicle control. However, it is important to note that at this optimal concentration , 2TAA hampered cell viability over time in culture making it an unsuitable media supplement for improving titer production (page 14, lines 21-25)
3TAA can be employed for use in a cell culture production process. The inventors have shown that 3TAA has provides a significant improvement in volumetric titer . Apoptotic pathways were not initiated , making 3TAA extremely valuable as a small molecule enhancer . Host cell lines stably / transiently producing a biotherapeutic of interest , can be cultured in the presence of 3TAA for improvement in protein yields . 3TAA can function as a culture additive. It can also form part of a chemical feed to administer to cells at a later stage in culture, to allow cellular resources to solely focus on protein production after a proliferation phase (see page 14, line 31 bridging line of page 15)
The sections do not provide support for no apoptotic induction between 1.6 mM and 5.2mM measured using a flow cytometer as claimed. This is new matter.
The Applicant submitted the thesis of Kalsi et al. and states page 176 is supplemental data. This is a post-filing reference. Figure 6.5 of the post-filing reference discloses apoptosis of cells cultured in 2.5 mM 3TAA. It does not provide support for no apoptosis between 1.6 mM and 5.2 mM as claimed.
An amendment to the claims or the addition of a new claim must be supported by the description of the invention in the application as filed. In re Wright, 866 F.2d 422, 9 USPQ2d 1649 (Fed. Cir. 1989). Applicant is required to cancel the new matter in the reply to this Office Action.
APPLCANT’S ARGUMENTS
The arguments state [0078] and [0080] provide support for the amended claim. Citing the Inventor’s thesis, the Applicant states “Dr. Kalsi conclude that 28.8% of the cells cultured in the presence of 0.8 mM 2TAA were corded to be undergoing early apoptosis…and halving the concentration of 2TAA still displayed apoptosis induction…while concluding 3TAA did not appear to induce apoptosis”.
EXAMINER’S RESPONSE
The arguments are not persuasive. The originally filed specification does not provide support for “without inducing apoptosis as measured using a flow cytometer to identify Annexin V on day 5 of cell growth”. This is new matter. In response to the post-filing thesis: The data presented in Figure 6.5 demonstrates an apoptotic population of cells when cultured in 2.5 mM 3TAA. While page 188 states “3TAA did not appear to induce apoptosis”, this is not commensurate with the data pointed to by the Applicant on page 176. The disclosure does not provide support for no apoptosis with 1.6mM-5.2mM 3TAA on day 5 as claimed.
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 8-12, 14 and 17-21 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.
Claims 8 and 10 have been amended to recite “… on day 5 of cell growth”. The claims do not recite cell growth. It is unclear if the claims are referring to the cell incubation recited in step (a). All dependent claims are included in this rejection.
Claim Rejections - 35 USC § 102
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 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.
Claims 8-12, 14 and 17-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kalsi et al. (High-Throughput Platform Development for Chinese Hamster Ovary (CHO) Cell Culture Performance Enhancement Using Small Molecules. 02 March 2019 pages 1-251).
Kalsi culture CHO cells (mammalian cells) with 2.5 mM 3TAA (see Figure 6.3 text page 172). Kalsi teaches culturing for 10 days (text below Figure 6.3). The supernatant is collected (see paragraph below Figure 6.3). Therefore the producer cell culture media is collected. Antibody (hence, product) levels are quantified (see same cited section). Kalsi analyzes cells using Annexin V (apoptosis indicator) on day 5 (see text of Figure 6.5). Figure 6.5 discloses titer and IVCD change on day 5. Because Kalsi anticipates the claimed method, it would inherently induce apoptosis as measured in claim 8.
Under the principles of inherency, if a prior art method, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art method. When the prior art method is the same as a method described in the specification for carrying out the claimed method, it can be assumed the method will inherently perform the claimed process. See In re Best, 562 F. 2d, 1252, 1255, 195 USPQ 430, 433 (CCPA 1977) and Ex parte Novitski, 26 USPQ 2d 1389 (Bd. Pat. App. & inter. 1993). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of the invention, but only that the subject matter is in fact inherent in the prior art reference. See Schering Corp. v. Geneva Pharm. Inc, 339 F.3d 1373, 1377, 67, USPQ2d 1664, 1668 (Fed. Cir. 2003). See also Toro Co. v. Deere & Co. 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004).
Therefore claim 8 is rejected.
Regarding independent claim 10: The claim recites a protein is produced. The teachings of Kalsi are reiterated. Kalsi teaches an antibody (hence, a protein) is produced. Therefore claim 10 is rejected on the same grounds as claim 8.
Kalsi teaches chemicals were added at the start of culture at mid-exponential phase (see page 50, first paragraph; page 169, last paragraph). The art taches basal media (see page 195, second paragraph. Therefore claims 9 and 12 are included in this rejection.
Kalsi teaches antibody is produced (supa). The art teaches it is a recombinant product (last paragraph of page 186). This anticipates a recombinant protein. Therefore claim 11 is included in this rejection.
Kalsi teaches 2.5 mM 3TAA (supra). Therefore claims 14, 17 and 20-21 are anticipated.
Figure 5.10G discloses 5.2 mM 3TAA. Therefore claims 18-19.
Therefore Applicant’s Invention is anticipated as claimed.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 8-12, 14 and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Allen et al. (previously cited; Identification of Novel Small Molecule Enhancers of Protein Production by Cultured Mammalian Cells. Biotechnology and Bioengineering, 100(6) 2008: 1193-1204) in view of Campaigne et al. (previously cited; 3-Substituted Thiophenes. Journal of American Chemistry, 1955. Volume 77:5365-5369).
Allen teaches adding small molecule additives to cell culture media that are capable of enhancing the expression of recombinant proteins have significant utility in the production and manufacture of therapeutic polypeptides (Abstract).
Allen uses 2-thienylacetic acid (2-TAA) as an additive. As evidenced by the instant specification, thienyl and thiophene are synonymous ([0040]). Therefore Allen uses 2-thiopheneacetic acid. As evidenced by the PG Pub of the Instant Specification, 2TAA is a structural analogue of 3TAA ([0060]). As evidenced by the PGPub at [0038]:
The term “analogue thereof” as used herein should be understood to mean a functional and/or structural analogue of 3TAA. A functional analogue is preferably a carboxylic acid molecule with a thiophene/thienyl group. A functional analogue of 3TAA should deliver at least a 1.5-fold increase in titer production versus control when used at its optimal concentration and at optimum time of deployment, with a cell growth reduction of no more than 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or preferably no more than 40%.
Because 2TAA contains a thiophene/thienyl group, it is also a functional analogue of 3TAA as evidenced by the specification.
Allen teaches 2-TAA increased titer production of monoclonal antibody produced by CHO cells (hence, mammalian cells) (see page 1198, left column, first paragraph). Allen teaches samples are collected to determine titer (see page 1195, left column, last paragraph). Because Allen teaches recombinant protein titer, the protein has been harvested. A protein reads on a product.
While 2-thiopheneacetic acid is used at a concentration of 0.5 mM (page 1196, right column, first paragraph), the art teaches a dose-response relationship (page 1196, right column, end of first paragraph). The art teaches generating a dose-response curve to determine the optimal working concentrations (0.3-0.6 mM) for aromatic carboxylic acids.
Allen does not teach using 3TAA as a small molecule additive in the cell culture method.
Allen does not teach the claimed amount of 3TAA.
Campaigne teaches “when a 3-thienyl group is substituted for a 2-thienyl group in a physiologically active compound, the activity of the 3-theinyl isomer is equal to, or greater than, that of the 2-thienyl derivative. In no case has decreased activity been observed in going from the 2-to the 3-thienyl substituent” (page 5365, left column, second paragraph). As evidenced by Campaign, 3-thienylacetic acid is an isomer of 2-theinylacetic acid (see page 5365, right column, first paragraph).
It would have been obvious to try using 3-TAA in the culture media taught by Allen. One would have been motivated to do so since Allen uses 2-TAA in a mammalian cell culture media and Campaign teaches the 3-thiophene isomer has an activity equal to or greater than the 2-thiophene isomer. The skilled artisan would do so to increase protein production in the cells taught by Allen. One would have had a reasonable expectation of success since Campaign teaches in no case has decreased activity been observed in going from the 2-to the 3-thiophene substituent. One would have expected similar results since both references are directed to the use of thiophene acetic acid derivatives.
It would have been obvious to try optimizing the amount of 3-TAA used in a culture media. Allen teaches aromatic carboxylic acids can be used at a working concentration of 0.3-0.6 mM, and teaches the effect of the additive is based on the dose. The skilled artisan would increase the dose taught by Allen to improve protein titer. In the absence of criticality, the claimed range would have been obvious. See MPEP 2144.05. Because the claimed media is rendered obvious, it would be expected to increased product titer without inducing apoptosis as recited. Therefore claim 8 is rendered obvious.
The concentrations recited in claims 14, 18 and 20 are rendered obvious on the same grounds.
Allen teaches cells are first cultured in a base media (page 1194, right column, first paragraph). Allen teaches small molecule enhancers are added on day 2 (page 1995, left column, last paragraph). Claim 9 recites the cells are first incubated with a basal cell culture media without 3TAA for a period of time until the cells are at mid to late exponential phase or early stationary phase. The specification states “In the specification, the term “period of time” should be understood to mean a period of incubation of 10 days or less, that is, a period of incubation of between 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days” ([0055] of PG Pub). Therefore Allen is interpreted to read on the claim. Even arguendo it did not, it would have been obvious to optimize the time in culture. One would have been motivated to do so to obtain the desired number of cells for analysis. Therefore claim 9 is included in this rejection.
Regarding independent claim 10:
The teachings of Allen are reiterated. Allen discloses 2TAA can be used in a culture media to enhance protein production in mammalian cells. The art is silent regarding the use of 3TAA.
The teachings of Campaigne are reiterated.
It would have been obvious to try using 3TAA in the culture media taught by Allen. One would have been motivated to do so since Allen uses 2TAA in a mammalian cell culture media and Campaign teaches the 3-thiophene isomer has an activity equal to or greater than the 2-thiophene isomer. The skilled artisan would do so to increase protein production in the cells taught by Allen. As evidenced by the specification, 2TAA and 3TAA are structural and functional equivalents. KSR B teaches that it is rational to substitute one known, equivalent element for another to obtain predictable results.
One would have had a reasonable expectation of success since Campaign teaches in no case has decreased activity been observed in going from the 2-to the 3-thiophene substituent. One would have expected similar results since both references are directed to the use of thiophene acetic acid derivatives.
It would have been obvious to try optimizing the amount of 3-TAA used in a culture media. Allen teaches aromatic carboxylic acids can be used at a working concentration of 0.3-0.6 mM, and teaches the effect of the additive is based on the dose. The skilled artisan would increase the dose taught by Allen to improve protein titer. In the absence of criticality, the claimed range would have been obvious. See MPEP 2144.05. Because the claimed media is rendered obvious, it would be expected to increased product titer without inducing apoptosis as recited. Therefore claim 10 is included in this rejection. The concentrations recited in claims 17, 19 and 21 are rendered obvious on the same grounds.
Allen produced a monoclonal antibody (sura). Therefore claim 11 is included in this rejection.
Allen teaches cells are first cultured in a base media (page 1194, right column, first paragraph). Allen teaches small molecule enhancers are added on day 2 (page 1995, left column, last paragraph). Claim 12 recites the cells are first incubated with a basal cell culture media without 2TAA for a period of time until the cells are at mid to late exponential phase or early stationary phase. The specification states “In the specification, the term “period of time” should be understood to mean a period of incubation of 10 days or less, that is, a period of incubation of between 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days” ([0055] of PG Pub). Therefore Allen is interpreted to read on the claim. Even arguendo it did not, it would have been obvious to optimize the time in culture. One would have been motivated to do so to obtain the desired number of cells for analysis. Therefore claim 12 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
APPLICANT’S ARGUMENTS
The arguments made in the response filed on 16 September 2025 are acknowledged. The Applicant argues it was surprisingly discovered 2TAA causes cells to enter into early apoptosis while 3TAA did not appear to induce apoptosis. The Applicant argues the post-filing reference (Kalsi thesis) demonstrates “0.4 mM and 0.8 mM 2TAA significantly increased apoptotic cell population while 2.5 mM 3TAA did not”.
EXAMINER’S RESPONSE
The arguments are not persuasive. Claim 8 is interpreted to mean no apoptosis is present in any amount at any concentration between 1.6-5.2mM. Figure 6.5A of the post filing refence discloses the percentage of cells that were apoptotic (Annexin V +ve but 7AAD -ve) out of all cell events recorded. While the percentage in the 3TAA treatment group appears lower, Figure 6.5A demonstrates apoptotic cells in all treatment groups. Figure 6.5B demonstrates an apoptotic population in the 3TAA treatment group. It is also noted the concentrations are not commensurate with the scope of the base claims. While the post-filing reference recites “3TAA does not appear to induce apoptosis”, this conclusory statement is not evidence. The data does not provide evidence of no apoptosis at 1.6 mM and 5.2 MM 3TAA.
The arguments state the Office alleges 3TAA has increased activity. The Applicant argues Examiner is incorrect. The Applicant states 3TAA has less activity. In response, Examiner notes Campaign teaches the following:
“when a 3-thienyl group is substituted for a 2-thienyl group in a physiologically active compound, the activity of the 3-theinyl isomer is equal to, or greater than, that of the 2-thienyl derivative. In no case has decreased activity been observed in going from the 2-to the 3-thienyl substituent” (page 5365, left column, second paragraph).
The statement made by Examiner is supported by the prior art.
While the Applicant argues “3TAA actually has less activity”, the specification does not provide support for this. The term “activity” is not found in the specification.
CONCLUSION
No Claims Are Allowed
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653