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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 16 September 2025 has been entered.
DETAILED OFFICE ACTION
This Office Action is in response to the papers 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 1, 3-4, 7 and 16-24 have been examined on their merits.
NEW GROUNDS OF 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 1, 3-4, 7 and 16-24 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 1 and 16 have been amended to recite the claimed product 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] if 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 as 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.
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 1, 3-4, 7 and 16-24 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 discloses a media comprising amino acids, sodium chloride (a salt) and glucose (page 1194, right column, first paragraph). As evidenced by the specification: amino acids are a nitrogen source and glucose is a carbon source (see [0056]). 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. Allen teaches 2-TAA increased titer production of monoclonal antibody produced by CHO cells (hence, mammalian cells) (see page 1198, left column, first paragraph).
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 discloses 2-TAA can be used in a culture media to enhance protein production in mammalian cells. The art is silent regarding the use of 3-TAA.
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 1 is rendered obvious. The concentrations recited in claims 3-4 and 17-18 are rendered obvious on the same grounds. Allen teaches a liquid culture media (see page 1195, left column, last paragraph). Therefore claim 7 is rejected.
Claim 16 is directed to a kit. A kit is a collection of components. As set forth above, Allen teaches a cell culture media and mammalian cells that produce protein. The use of 3-TAA is rendered obvious on the grounds set forth in the rejection of claim 1. The range recited in claim 16 is rendered obvious on the grounds set forth above. Because the claimed media is rendered obvious, it would be expected to increased product titer without inducing apoptosis as recited. Therefore claim 16 is included in this rejection. The concentrations recited in claims 19-22 are rendered obvious on the same grounds. Allen teaches CHO cells (supra). Therefore claim 23 is rejected. Allen teaches a liquid culture media (see page 1195, left column, last paragraph). Therefore claim 24 is rejected.
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 1 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.
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) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653