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 ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Nov. 12, 2025. Claims 19, 21-27 and 29-40 are pending and currently examined.
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.
(Previous Rejection – Maintained) Claims 19, 21-27 and 29-40 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.
The base claim 19 specifies “wherein said antibody inhibits cell-to-cell spread when less than 20% of the adjacent cells are infected.” This limitation is not clear as to how the limitation “when less than 20% of the adjacent cells are infected” should be interpreted. E.g., it is not clear what should be used as the reference location to determine if a cell can be considered as adjacent, and under what condition the antibody inhibition of cell-to-cell spread is tested (e.g., what antibody titer is used, on what host cells, in vitro or in vivo, etc.).
Applicant argues that in the Declaration, Dr. Welschorf explains that “cell-to-cell spread” and “adjacent” are phrases well understood, that the description and assays provided in the Specification are consistent with what was known in the art, and that no further explanation or description is needed for POSITA to understand the metes and bounds of the claims.
Applicant’s arguments are not persuasive. Dr. Welschorf explains about the limitation “wherein said antibody inhibits cell-to-cell spread when less than 20% of the adjacent cells are infected” in paragraphs 15-21, arguing that in 2014 it is well understood to him and a POSITA what was meant by “cell-to-cell” inhibition, how inhibition assays were to be carried out, and how to identify “adjacent” cells. It is noted that the rejection is not only on how the phrases and assays are to be explained, but also about how the phrases are to be used in defining the scope of the claims. E.g., Applicant does not address the issue how to determine if “less than 20% of the adjacent cells are infected” when it is not clear what should be used as the reference location to determine if a cell can be considered as adjacent, and under what condition the antibody inhibition of cell-to-cell spread is tested (e.g., what antibody titer is used, on what host cells, in vitro or in vivo, etc.).
Claim Rejections - 35 USC § 103
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 of this title, 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.
(Previous Rejection – Maintained) Claims 19, 21-25, 29-30, 34 and 37-40 are rejected under 35 U.S.C. 103 as being unpatentable over Haynes et al. (US 2014/0302062 A1, published on Oct. 9, 2014, PCT filed on April 9, 2012) in view of Betz (WO 2005/023303 A1, published on March 17, 2005) and/or Chen et al. (US 2011/0033389 A1, published on Feb. 10, 2011).
(Previous Rejection – Maintained) Claims 25-27 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Haynes et al. (US 2014/0302062 A1, published on Oct. 9, 2014, PCT filed on April 9, 2012), Betz (WO 2005/023303 A1, published on March 17, 2005), and/or Chen et al. (US 2011/0033389 A1, published on Feb. 10, 2011), as applied above, in view of Krawczyk et al. (PNAS, 110(17): 6760–6765, April 23, 2013; submitted in IDS filed on Feb. 18, 2022) and/or Roggendorf et al. (US 2013/0058952 A1, published on Mar. 7, 2013).
Applicant argues that central to both rejections are Haynes, Betz and Chen, and that, as explained by Dr. Welschof, these references do not render the claims obvious when one considers the art as a whole. Applicant argues that (1) a POSITA would not have expected a topically applied antibody would be effective in treating an acute HSV infection, (2) full-length antibodies were administered by IV or subcutaneously, and (3) topical administration of antibodies required engineering, co-administration with permeability factors, or fragment of the full-length antibody. Applicant argues that Dr. Welschof also states that the use of pooled IgG fractions from serum leads to questions as to what exactly is causing the activity in the serum, and that he makes this conclusion when noticing the inconsistent results reported between Haynes, Betz and Krawczyk.
Regarding argument (1), Applicant states, by Declaration of Dr. Welschof in paragraphs 23-28, that Krawczyk demonstrated that pooled full-length antibodies did not inhibit HSV-1 or HSV-1 infection, citing Figure 3 which demonstrates that in the presence of pooled human polyclonal sera, neither HSV-1 nor HSV-2 transmission could be sufficiently blocked (Panels A and B), that, instead, the authors observed extensive virus spread with plaque formation on Vero cell monolayers which indicated that the antibodies contained within the polyclonal sera were ineffective in preventing virus spread. Applicant argues that similarly, the authors of Thiel also reported that whole IgG of 146kDa had no detectable penetration of cornea when topically applied. Applicant argues that, full-length antibodies were thought to be too large in size to penetrate or cross the extracellular and cellular barriers of the epidermis or mucosa to be effective in topical administration.
These arguments are not persuasive. As to Applicant’s argument that Krawczyk demonstrates that antibodies contained within the polyclonal sera were ineffective in preventing virus spread, it is worth noticing that the claim limitation of inhibiting cell-to-cell spread does not specify to what extent the neutralizing and inhibiting capability should be. A weak activity would suffice. Therefore, the observation of Krawczyk that antibodies in the pooled polyclonal sera were ineffective in preventing virus spread in cultured cells does not necessarily indicate that the polyclonal antibodies in pooled sera do not have the activity to “inhibit cell-to-cell spread” of HSV viruses. On the other hand, Krawczyk teaches explicitly that mAb hu2c completely inhibited cell-to-cell spread of both HSV-1 and HSV-2 viruses (see page 6762, right column, para 1), indicating that full-length antibodies can have the ability to block spreading of HSV in cultured cells.
As to Applicant’s argument based on Thiel et al. (Clin Exp Immunol. 128:67-742002), it is first noticed that the results are based studies on cornea while the invention as claimed are more on the skin- or mucosa-related HSV infections. There is no indication that results obtained on the cornea penetration may be applied to the skin or mucosa infections. This is especially true with the diseases to be treated as claimed, such as the acute infection of herpes simplex labialis which happen on the surface of infected skin which is different in structure from the cornea.
Regarding arguments (2) and (3), Applicant states, by Declaration of Dr. Welschof in paragraphs 28-35, that Krawczyk administered full-length antibody intravenously (and not topically) to overcome this hurdle (of poor penetration), and that POSITAs in 2014 did not expect that a full-length anti-HSV antibody could inhibit cell-to-cell spread in a HSV acute infection when topically applied; Applicant further states, by the Declaration, referring to other provided references (e.g., Stevens & Cowin, Sprunance et al., Gilbert et al., Freeman and Spruance, etc.), that skin constitutes a barrier to the topical delivery of antibodies, largely due to the hydrophobic nature of the outer keratinized layer, which prevents delivery of hydrophobic and polar compounds such as proteins, and that subcutaneous injection was predominant alternative delivery route (instead of IV delivery), and commonly used to treat immunological chronic diseases, such as asthma, rheumatoid arthritis and psoriasis, and that other administration routes of marketed Ab include intravitreal application in ophthalmic disorders, inhalation, and intra-articular which constitute a growing focus of research for local-acting antibodies.
Applicant’s arguments are not persuasive. First, it is noted that most of the examples (from the cited references) deal with HSV infections associated with diseases other than those as claimed, which affect the topical layer of the skin or mucosa. E.g., Thiel et al. (Clin Exp Immunol. 128:67-742002) focuses on penetrating the cornea which is not comparable with HSV-infected skin or mucosa, such as herpes simplex labialis, as claimed; Stevens & Cowin (Wound Practice and Research, 25(4): 188-194, 2017) reviews about challenges of topical antibody administration for improving wound healing outcomes; Gilbert et al. describes about antibody topical therapy for basal cell carcinoma; and Spruance et al. (Antimicrobial Agents and Chemotherapy, 1984, 25(1): 10-15) reports a study on topical therapy of experimental cutaneous HSV infection with acyclovir, a small molecule drug, not full-length antibodies; etc. When arguing about the barrier for full-length antibody penetration, Applicant has not considered the differences between the diseases to be treated by the claimed invention and those described in the referenced studies.
On the other hand, Betz (WO 2005/023303A1, cited in the current rejections) teaches topical application of IgG prepared from pooled human plasma for the treatment of herpes digitalis, herpes facialis, herpes genitalis, herpes gladiatorum, and herpes stomatitis. Teachings of Betz indicate that topical application of full-length antibodies, i.e., IgG prepared from pooled human plasma, for the treatment of skin and mucosa herpes infections is contemplated and practiced at the time of invention. Applicant’s argument that the use of pooled IgG fractions from serum leads to questions as to what exactly is causing the activity in the serum is not persuasive. Applicant has not provided convincing evidence what in the pooled IgG fractions from serum other than the antibodies against HSV may cause the effect of treating the HSV infection, while many other references, including ones cited in the current rejections and those provided by Applicant, indicate that HSV-specific antibodies block cell-to-cell spread of the virus and inhibit the infection.
Applicant argues, by Declaration of Dr. Welschof in paragraphs 36-37, that the Specification unexpectedly demonstrates that a full-length antibody, topically applied, can have a beneficial and unexpectedly active effect, referring to Figures 1 and 2. Applicant argues that if topical application of full-length antibody was obvious to the skilled artisan, it should have been attempted previously.
Applicant’s arguments are not persuasive.
As to applicant’s arguments about unexpected results, as an initial matter, “the burden of showing unexpected results rests on he who asserts them. Thus it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted). Applicant’s attention is directed to MPEP 716.02(b)-(e) for how unexpected results can be established. E.g., to evaluate if the claimed invention produces unexpected results, one must consider if the results produced by the claimed invention are commensurate in scope with the claims and how the results compare with the closest prior art. See MPEP Section 716.02(d) and (e). Here, Applicant has not provided sufficient information for the Office to consider if the results produced by the claimed invention are commensurate in scope with the claims and how the results compare with the closest prior art.
Additionally, MPEP 2145 II teaches that prima facie obviousness is not rebutted by merely recognizing additional advantages or latent properties present but not recognized in the prior art. Figures 1 and 2 of the specification indicate that topic administration of a humanized monoclonal antibody, hu2c, is effective in protecting or treating mice with genital HSV infections. This showing of effectiveness is associated with the properties of the hu2c antibody which is known at the time of invention. Here the combined teachings of Haynes, Betz, Chen, Krawczyk and Roggendorf suggest the claimed method of topical administration of acute HSV infections as claimed. The treatment effect shown in Figures 1 and 2 is a latent property of the art-known antibody hu2c that is silent in the cited references and does not rebuttal the obviousness of the claimed invention.
As to Applicant’s argument that topical application of full-length antibody should have been attempted previously if it was obvious to the skilled artisan, it is noted that the current rejection is an obviousness rejection. Only an anticipation rejection under 35 U.S.C. 102 requires such an attempt be known publicly before the effective filing date of the current rejection.
Conclusion
No claims are allowed.
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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/ Primary Examiner, Art Unit 1671
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