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 1-4, 6-7, 10-11, 13, 15-16, 19-23, 28, 30, 33-34, 36, 38, and 40-41 are pending and subject to examination on the merits. Claims 1-4, 6-7, 10-11, 13, 15-16, 19-20, 22-23, and 41 are withdrawn from consideration as being drawn to non-elected subject matter. Claims 21, 28, 30, 33-34, 36, 38, and 40 are currently under examination.
Election/Restrictions
2. Applicant’s election without traverse of group II (Claims 21, 28, 30, 33-34, 36, 38, and 40) in the reply filed on 27 May 2026 is acknowledged.
Priority
3. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 63/191,781 filed 21 May 2021.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted on 07 September 2021 and 12 July 2022 have been considered by the examiner. See initialed and signed PTO/SB/08’s.
Claim Rejections - 35 USC § 112(a)
5. 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.
Written Description:
6. Claims 21, 28, 30, 33-34, 36, and 38 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 claim(s) contains 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a method of producing an unknown recombinant product of interest (except in claims 33-34 and 36) in an unknown modified cell (except claim 40), wherein said cell is modified to reduce or eliminate the expression of two or more unknown endogenous proteins that normally function to promote apoptosis and regulates the unfolded protein response, and wherein the modified cell that expresses the recombinant product of interest exhibits reduced and/or eliminated expression of BAX, BAK, and PERK.
MPEP 2163(1):
35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en bane); Vas-Gath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111, 1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim's enablement is not equally conclusive of that claim's satisfactory written description"). The written description requirement has several policy objectives. "[T]he 'essential goal' of the description of the invention requirement is to clearly convey the information that an applicant [inventor] has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). "The 'written description' requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor's obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee [inventor] was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent's term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Gath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. However, a showing of possession alone does not cure the lack of a written description. Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 969-70, 63 USPQ2d 1609, 1617 (Fed. Cir. 2002). For example, it is now well accepted that a satisfactory description may be found in originally-filed claims or any other portion of the originally-filed specification. See In re Koller, 613 F.2d 819, 204 USPQ 702 (CCPA 1980); In re Gardner, 475 F.2d 1389, 177 USPQ 396 (CCPA 1973); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). However, that does not mean that all originally-filed claims have adequate written support. The specification must still be examined to assess whether an originally-filed claim has adequate support in the written disclosure and/or the drawings.
7. The claims are drawn to a method of producing a huge number of recombinant products by a large and variable number of cells with reduced or eliminated expression of a large and variable genus of apoptotic promoting and UPR regulating proteins. The variability in reduced expression of any two proteins in addition to producing any product in any cell is enormous. The specification does not describe the production of any number of products in any number of cells with reduced endogenous expression of two or more endogenous proteins and reduced or eliminated expression of BAX, BAK, and PERK. At most the specification describes a single, double, and triple knockout of BAX, BAK, and PERK in CHO cells and the subsequent production of mAb3 and Fab1 in those cells (Example 4). However, how a modified CHO cell produces mAb3 and Fab1 says nothing about the method of producing any other possible recombinant product in any other type of modified cell, wherein the modification could be any two or more endogenous proteins involved in the regulation of UPR and apoptosis. Here the specification is incomplete and it mandates that those skilled in the art must then figure out how to use the aimed invention. Thus, the claims do not find adequate support in any place in the specification to show the possession of methods to produce any recombinant product in any modified cell. The courts have established:
Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336 (Fed. Cir. 2013):
A patent, however, "is not a reward for the search, but compensation for its successful conclusion." Ariad, 598 F.3d at 1353 (quoting University of Rochester, 358 F.3d at 930 n.10). For that reason, the written description requirement prohibits a patentee from "leaving it to the ... industry to complete an ufinished invention.” Id.
Enablement:
8. Claims 21, 28, 30, 33-34, 36, and 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the methods of a single, double, and triple knockout of BAX, BAK, and PERK in CHO cells and the subsequent production of mAb3 and Fab1 in those cells (Example 4), does not reasonably provide enablement for all of the different recombinant products that could be produced by any type of modified cell, i.e. a cell with reduced or eliminated endogenous proteins involved in apoptosis and the UPR and reduced BAX, BAK, and PERK. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims without significant undue experimentation.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states:
"Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims in their broadest are drawn to a method of producing any recombinant product of interest in any modified cell, wherein said cell is modified to reduce or eliminate the expression of two or more unknown endogenous proteins that normally function to promote apoptosis and regulates the unfolded protein response, and wherein the modified cell that expresses the recombinant product of interest exhibits reduced and/or eliminated expression of BAX, BAK, and PERK. The direction and guidance coupled with the working examples of the application, however, are drawn only to demonstrating two specific working examples of recombinant protein production, specifically the utilization of CHO cells with reduced BAK, BAX, and/or PERK to produce mAb3 and Fab1. The quantity experimentation would be considerable because, while the relative skill level in the art is high (PhD or MD), they would be required to ascertain what cells, specific endogenous pro-apoptotic proteins, and what recombinant products to produce in the claims. It would be extremely difficult to be able to discern what products to make, utilizing what cells and what specific endogenous proteins to reduce the expression thereof, resulting in an excessive trial and error to produce the recombinant products. It would be almost impossible to reliably predict the combination and/or combinations necessary to produce all of the different products claimed in the application.
Claim Rejections - 35 USC § 112(b)
9. 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.
10. Claims 21, 28, 30, 33-34, 36, 38, and 40 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.
11. Claim 21 (part (b) last line) recites “reduced or eliminated expression…” without a comparison, i.e. a wildtype or unmodified cell. To mitigate this issue, see part (a) which does recite “relative to.” Claims 28, 30, 33-34, 36, 38, and 40-41 are included in the instant rejection because they do not resolve the issue.
12. Claim 21 recites the limitation "the modified cells" in part (b). The claim recites a modified cell and the modified cell but not the plural thereof. Claims 28, 30, 33-34, 36, 38, and 40-41 are included in the instant rejection because they do not resolve the issue.
13. Claim 28 recites “the modified cells” in part (ii). It is unclear what cells are being referenced here. The claim recites the modified cell but not the plural thereof.
14. Claim 34 recites “wherein antibody” in line 1. It is unclear if “wherein antibody” is referring to “the antibody” from claim 33 or “an antibody-fusion,” which would not be the same antibody as recited in claim 33. To mitigate this issue, amend the claim to recite “an” or “the.”
Claim Rejections - 35 USC § 103
15. 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.
16. 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.
17. Claims 21, 28, 30, 33-34, 36, 38, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Rossomando et al (Rossomando et al., 2011, WO 2011005786 A2—cited herein). Regarding claim 21, drawn to producing a product of interest comprising: (a) culturing a modified cell, wherein the cell is modified to reduce or eliminate the expression of two or more endogenous proteins compared to an unmodified cell by applying a nucleic acid; wherein (i) one or more of the endogenous proteins promotes apoptosis, and (ii) one or more to the endogenous proteins regulates the unfolded protein response (UPR), and (b) recovering the recombinant product of interest from medium or modified cells, wherein the modified cell expressing the recombinant product of interest exhibit reduced or eliminated expression of BAX, BAK, and PERK, Rossomando et al. teaches the enhancement of a biological product in a host cell by modulating the expression of a target gene in the cell, including one or more oligonucleotides, such as RNA effector molecules, which inhibit the expression of the target gene, targeting apoptosis and/or cell cycle progression (paragraphs 0009-0010), where although the inhibition is temporary; . Additionally, Rossomando et al. teaches the targeting of at least BAX, BAK, and LDH with PERK (claims 4, 6, and 77), where Rossomando et al. teaches that BAX and BAK are involved in the regulation of apoptosis in CHO cells, reducing the rate of apoptosis by 300% (Fig. 13; paragraph 0111) and PERK is involved in the UPR pathway (paragraph 0188). Regarding claims 28 and 30, drawn to the method of claim 21, wherein the recombinant product of interest is encoded by a nucleic acid integrated into the cellular genome of the modified cell and further where the recombinant product comprises a viral particle, Rossomando et al. teaches the infection of a cell with a retrovirus, where reverse transcriptase makes a DNA copy of the RNA, where this RNA is then integrated into the host’s genome (paragraph 0213). Regarding claims 33-34 and 36, drawn to the recombinant product of interest being an antibody, multi-specific antibody, or a chimeric antibody, Rossomando et al. teaches the biological product is a humanized antibody, derivative thereof, bispecific, or a chimeric antibody (paragraph 0228). Regarding claim 38, drawn to the purification of the product of interest, Rossomando et al. teaches kits further comprising reagents for purifying the biological product (paragraph 0043). Regarding claim 40, drawn to the utilization of CHO cells as the modified cell, Rossomando et al. teaches the host cell can be CHO cells (paragraph 0086).
Rossomando et al. do not teach, however, a specific example of a method of producing a recombinant product in a cell where BAK, BAX, and PERK are deleted. Nonetheless, 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 various teachings of Rossomando et al. to devise a method to enhance the production of a biological product by utilizing a modified cell, wherein said cell has been modified with nucleic acids targeting one or more endogenous genes, wherein said targeted genes are involved in the regulation of apoptosis and the UPR, and wherein the expression of BAK, BAX, and PERK are reduced to optimize cell culture bioprocesses involving a wide range of host cells and biological products as taught by Rossomando et al (paragraph 0005). One would be motivated to combine these teachings to arrive at the instant claims to enhance the production of a bioproduct through the downregulation of apoptotic and UPR involved proteins, such as BAK, BAX, and PERK to enhance productivity, yield, efficiency to facilitate industrial scale production as taught by Rossomando et al (paragraph 0005). There would be reasonable expectation of success, yielding no surprising results when combining the collective teachings of Rossomando et al. to utilize a method involving a cell with downregulated BAX, BAK, and PERK gene products to produce a biological product because Rossomando et al. teaches the downregulation of these gene products and the subsequent purification thereof.
Conclusion
18. All claims are rejected.
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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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
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