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 Claims
The amended claims filed 12/03/2025 are acknowledged and entered.
Claim 9 has been amended
Claims 1-8, 10 and 18 are cancelled
Claims 9 and 13-17 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Claim Rejections - 35 USC § 102 - Withdrawn
2. The rejections of claims 1-8, under 35 U.S.C. 102(a)(b) as anticipated by WO/2009/134027 (PCT/KR09/01973). and the rejections of claims 1-2, 4, 7, 9, 13, 15 and 18, under 35 U.S.C. 102(a)(b) as anticipated by WO/2008/035894 (PCT/KR2007/004498) are all withdrawn in view of Applicant’s cancellation of claims 1-8 and 18 and an amended claim 9.
Double Patenting - Withdrawn
5. The rejections of claims 1-8 on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of copending application US 18/021,989. (reference application). are withdrawn in view of Applicant’s cancellation of claims 1-8.
New Objections
Claims 9 and 14 are objected to because of the following informalities:
Claim 9 recitation’s clarity is improved by the following changes:
- Adding “monoclonal” to the limitation in line 5 “..an antibody or a functional fragment thereof…” So, the recitation reads “ …a monoclonal antibody or a functional fragment thereof…”.
- “Represented by” to be changed to “comprising of”.
Claim 14 the recitation “…comprising an amino acid sequence…” to be changed to “… comprising the amino acid sequence…” to maintain consistency with claims 13 and 16.
Appropriate correction is required.
Claim Rejections - 35 USC § 103 - Maintained
Claims 9 and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over WO/2009/134027 (PCT/KR09/01973, previously cited) in view of WO/2008/035894 (PCT/KR2007/004498, previously cited) and Gorbalenya (previously cited).
WO/2009/134027 teaches the identical antibody, named 3D8 ([104-132], example 1, claims 5-12)), as shown in the sequence alignments (see Non Final Action mailed on 08/04/2025) for the CDRs, VH, VL and scFv sequences with the SEQ ID NOs recited in instant claims 9, 13-14 and 16 (SEQ ID NOs 1-9). WO/2009/134027 also teaches that the fragments of the immunoglobulin are selected from the group consisting of scFv, VH, VL and, Fv in which VH is associated with VL, as required in instant claim 15. The antibody can be a chimeric antibody [40] or a humanized antibody [45] as required in instant claim 17.
WO/2009/134027 does not teach the use of the antibody as an antiviral composition or a method to treat a coronavirus infection disease as required by instant claims 9 and 13-17. However, It would be an inherent property for the antibody in WO/2009/134027 to bind the same antigen for the anticancer activity as for the antiviral (coronavirus including SARS-CoV-2, hCoV-OC43 and PEDV) since the antibody has a nuclease activity (specification [53]) and because the structure confers the binding ability. "Applicant is reminded that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01" as required in instant claim 9.
WO/2008/035894 teaches a nearly identical antibody, also named 3D8 ([27-29], [32-40], [43-44], [46-59], example 1, claim 13-16) with just two mismatches in the framework region of the VL chain (and therefore these mismatches are also found in the scFv antibody), please see the alignments found in the Non Final Action mailed on 08/04/2025 for the VL and scFv for SEQ ID NO: 7 (VH at 100% identify), SEQ ID NO: 8 (VL with a 98.8% identity) and SEQ ID NO: 9 (scFv with 98.3% identity). The sequence alignments for the instant SEQ ID NOs 1-7 showing 100% identity have also been discussed in the Non Final Action mailed on 08/04/2025 (instant claims 9, 13 and 14). In addition, WO/2008/035894 teaches that the claimed antibody exhibits anti-virus activity against SARS virus (a beta-coronavirus) ([92], [342] and claim 9) as required in instant claims 9, 13-17. WO/2008/035894 also teaches that the immunoglobulin fragment is selected from scFv, VH, VL, and Fc with an association of VH and VL (WO/2008/035894 claim 12) as required in instant claim 15. WO/2008/035894 also teaches effective dosages of the protein for treatment ([114]- [117]) and delivery routes ([120} and [122]) (that is, a method of treatment, instant claims 9 and 13-17).
WO/2008/035894 does not teach the virus being a coronavirus selected from the group of SARS-CoV-2, hCoV-OC43 and PEDV as required in instant claim 9.
Gorbalenya teaches the identification and phylogeny of SARS-CoV-2 within the Coronaviridae (entire article). SARS-CoV-2 clusters with SARS-CoV in trees of the species Severe acute respiratory syndrome-related coronavirus (figure 2b) and the genus Betacoronavirus (figure 2c).
It would have been obvious to one of ordinary skill in the art to combine the teachings of WO/2009/134027, WO/2008/035894 to develop an antiviral composition, the 3D8 antibody, to treat a coronavirus disease (claims 9) because there is only two amino acid mismatch between the antibody taught by WO/2009/134027 and the nearly identical antibody (with the same name) taught by WO/2008/035894 and these mismatched amino acids are framework residues located only in the VL domain of the antibody. One of ordinary skill would have been motivated to do so because both antibodies shared the same CDRs and therefore bind the same epitope. In addition, both antibodies show the same nuclease function: WO/2009/134027 teaches in example 11 that there is RNA damage caused by the 3D8 scFv protein having a nuclease activity when it permeates into the cells [195]. WO/2008/035894 figure 23 teaches the RNase activity of 3D8 scFv [47]. This conclusion of obviousness is supported by KSR rationale (B) Simple substitution of one known element for another to obtain predictable results (see MPEP 2143, Supreme Court decision in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007)). In this case, substituting the WO/2009/134027 3D8 scFv with the WO/2008/035894 3D8 scFv. There would be a reasonable expectation of success because these two amino acid substitutions do not affect antibody binding to the epitope, which is needed for the nuclease function (the predicable result). It would further be obvious to combine WO/2009/134027, WO/2008/035894 with Gorbalenya and test the claimed antibody against SARS-CoV-2. One of ordinary skill would have been motivated to do so because the antibody taught by WO/2008/035894 is effective against SARS, and SARS and SARS-CoV-2 are very closely related virus as taught by Gorbalenya. In addition, the antibody taught by WO/2009/134027 is 100% identical to the claimed antibody so it would have the same antigen binding properties (method of treating SARS-CoV-2, hCoV-OC43 and PEDV by means of binding the same antigen) activity as well because the structure confers the binding ability. Applicant is reminded that products of identical composition cannot have mutually exclusive properties as discussed above. There would be a reasonable expectation of success because the antibody taught by WO/2008/035894 has been shown to be effective against a very wide range of DNA and RNA viruses and the antibody taught by WO/2009/134027 is 100% identical to the instant antibody.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Relevant arguments
Applicant’s arguments are as follow:
- (a) Gorbalenya et al. teaches that SARS-CoV-2 is phylogenetically related to SARS-CoV, and on WO 2008/035894, which generically mentions "SARS virus" as an example of RNA virus susceptible to the disclosed antibody. However, the cited references fail to disclose, suggest, or reasonably predict the claimed therapeutic method for treating SARS-CoV-2, hCoV-OC43, or PEDV. The Gorbalenya reference is a taxonomic and phylogenetic classification paper, not a therapeutic teaching. It provides no discussion of dosing, delivery, toxicity mitigation, or clinical effectiveness, and therefore cannot supply the missing therapeutic motivation or expectation of success required under §103. Consequently, the Examiner's reliance on mere sequence or taxonomic relatedness between viruses is insufficient to meet the initial burden of establishing a prima facie case of obviousness..
- (b) The claimed invention involves an unpredictable biological field. In the biotechnology and pharmaceutical arts, unpredictability of biological systems weighs heavily against a finding of obviousness. As stated in MPEP§ 2141 and MPEP§ 2145 (C), even when the prior art discloses similar compositions, "the prior art must provide not only a motivation to make the claimed invention, but also a reasonable expectation of success." The Examiner's rationale presumes that antiviral activity against SARS-CoV in WO 2008/035894 would have led a skilled artisan to reasonably expect success against SARS-CoV-2. This presumption is scientifically unsupported and legally untenable in view of the demonstrated unpredictability of coronavirus therapeutics.
- (c) Treatments effective or tested for SARS-CoV were not predictive of those effective for SARS-CoV-2. Scientific evidence shows that even closely related beta-coronaviruses exhibit markedly different pathogenic mechanisms and treatment responses. The comparative review by Keshta et al. (J Infect Public Health. 2021 Jul;14(7):967-977. Epub 2021 Apr 24.) summarizes: "Although both viruses arose from similar origins, they quickly diverged due to
differences in their transmission dynamics, spectrum of clinical presentations, and response to treatments."
During the 2003 SARS outbreak, treatments such as ribavirin, interferons, and lopinavir/ritonavir were empirically tried, yet results were inconsistent and largely inconclusive (Stockman et al., CMAJ 2006). By contrast, the treatment of COVID-19 (SARS-CoV- 2) relies on entirely different therapeutic agents-notably remdesivir, nirmatrelvir/ritonavir, corticosteroids, and immunomodulators-identified only after extensive post-2020 clinical trials (NIH COVID-19 Treatment Guidelines, 2024). Thus, treatments "effective" or investigated for SARS-CoV were not predictive of success against SARS-CoV-2.
- (d) Applicant's data demonstrate unexpected results. The present specification provides experimental results showing that the claimed antibody comprising the CDRs of SEQ ID NOs: 1-6 inhibits replication of SARS-CoV-2, hCoV- OC43, and PEDV by more than 99 % while exhibiting negligible cytotoxicity. These effects were unexpected given that prior 3D8 antibodies were reported to be cytotoxic rather than therapeutically antiviral. Under In re Soni, such unexpected properties rebut any prima facie case of obviousness.
Because the Examiner's reasoning relies solely on phylogenetic relatedness and fails to provide (1) an enabling therapeutic teaching or (2) a reasonable expectation of success, no prima facie case of obviousness has been established. Moreover, the field's inherent unpredictability- supported by Keshta et al. and by the divergent therapeutic outcomes for SARS-CoV and SARS- CoV-2
Applicant’s arguments have been considered but are not persuasive. In response to Applicant’s arguments:
- Regarding item (a), The instant claims do not recite any limitation regarding dosing, delivery, toxicity mitigation, or clinical effectiveness, Therefore, these parameters are not relevant to the instant claim examination or to a determination of a reasonable expectation of success. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Whereas Gorbalenya teaches SARS and SARS-CoV-2 are very closely related virus, WO/2009/134027 and WO/2008/035894 disclose the therapeutic teachings of the limitations in the instant claims (method of treatment using the instant antibody). Applicant has not sufficiently described why there is no prima facie case for obviousness, (since the antibody taught in WO/2009/134027 is exactly the same as the instant antibody), or why the conclusion of obviousness is not supported by KSR rationale (B). See discussion above for more details regarding the teachings of WO/2009/134027, WO/2008/035894 and Gorbalenya relevant to the rejection under 35 U.S.C. 103 and the motivation to combine these references. There is also no dose required by the claims. Therefore, Applicant’s arguments are not commensurate in scope with the claims.
- Regarding item (b), The antibody claimed in WO/2009/134027 is 100% identical to the instant claimed antibody and as disclosed above, these two antibodies inherently have the same chemical properties. That is, these antibodies will bind to the same antigen. The antibody taught in WO/2008/035894 has just two mismatches in the framework region of the VL chain (98.8% identity), that is all 6 CDRs and the VH chain are identical and thus, it will also bind the same antigen. In the biotechnology and pharmaceutical arts, there is no unpredictability (against a finding of obviousness) of antibodies when the antibodies are identical, and/or when the CDRs plus the VH chain are identical. A skilled artisan would assume a reasonable expectation of success as explained above. The burden is not a “definite” expectation of success but a reasonable one as it is in the instant application case. In addition, Applicant has failed to argue against the conclusion of obviousness as supported by the KSR rationale (B) Simple substitution of one known element for another to obtain predictable results In this case, substituting the WO/2009/134027 3D8 scFv with the WO/2008/035894 3D8 scFv. See discussion above for more details regarding the teachings of WO/2009/134027, WO/2008/035894 and Gorbalenya relevant to the rejection under 35 U.S.C. 103, KSR rationale (B) and the motivation to combine these references. Furthermore, as discussed above the antibody functions against a variety of viruses and its mechanism for RNA damage therefore does not rely on a specific epitope in SARS-CoV-2, for example.
- Regarding item (c), Applicant claims that treatments effective or tested for SARS-CoV were not predictive of those effective for SARS-CoV-2. However, Keshta and the NIH COVID-19 Treatment Guidelines teachings were published on April, 24, 2021 and 2024 respectively, after the effective filing date of the invention and therefore not known to the applicant or the skilled artisan at the time of the invention. In addition, both the conclusions of Keshta and the 2024 guidelines regarding treatment are generic and do not address specifically the instant antibody when compared to the WO/2009/134027 and WO/2008/035894 antibodies. Stockman teaches that ribavirin, interferons, and lopinavir/ritonavir were used during the 2003 SARS outbreak but none of these agents are antibodies (and thus, they are not related to the instant antibody) so the treatment results obtained with Direct Antiviral Agents (DAA) such as proteinase inhibitors, or immunomodulators such as interferon, or ribavirin are not comparable to results obtained with antibodies since the mechanisms of action are different and not necessarily related. Said another way, Applicant’s arguments concerning small molecule is not commensurate in scope with the claims drawn to antibody therapy.
- Regarding item (d), Applicant claims unexpected results. However, Applicant has not provided any cytotoxic and antiviral data comparing the instant antibody with the antibodies claimed by WO/2009/134027 and WO/2008/035894. Thus, no comparison has been made with the closest prior art. Applicant has not provided any explanation as to why a 100% identical antibody and/or an almost identical antibody (98.8% identity in the VL and 100% identical CDRs and VH chain) would be cytotoxic when compared to the instant antibody. Furthermore, a showing of unexpected results (cytotoxic and antiviral data) must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements that claimed compound possesses unusually low immune response or unexpected biological activity that is unsupported by comparative data held insufficient to overcome prima facie case of obviousness). MPEP § 2145. A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). MPEP 716.02 (a). The evidence relied * > upon < should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). MPEP 716.02 (b). Applicant must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). MPEP 716.02 (b). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). Applicant has failed to provide evidence of unexpected cytotoxic and antiviral data in comparison with the administration of prior art antibodies.
Also, Applicant’s arguments over side effects/cytotoxicity are moot in view of the fact the prior art uses the antibody therapeutically and so that it can be used safely is not shocking. Furthermore, no safety requirement is in the claims and such information only applies on a population level, not on the level of a single subject. Thus, no surprising result for lack of cytotoxicity/unwanted side effects are present.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671