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
The claim set filed 03/07/2023 is acknowledged. The response to election / restriction filed 01/30/2026 is acknowledged. The applicant elected Claims 1-13, drawn to a method of treating a ILC2 mediated disease comprising administering a KLRG1 binding agent or KLRG1 ligand binding agent, and species A, Asthma (including allergic airway disease, airway hyperreactivity) reading on claims 11-13. Claim 1 (and its dependent claims 2-10) are generic for this species election.
Claims 14-38 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/30/2026 5.
Claims 1-13 will be examined on the merits herein.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 4, 6, and 8 are rejected under 35 U.S.C. 102(a)(1) and 102 (a)(2) as anticipated by Greenberg et al. (US 20190085083 A1 from IDS filed 6/30/2023) as evidenced by Mojic et al., (Innate lymphoid cells: Dual roles and therapeutic opportunities in breast cancer. Immunol Lett. 2025 Dec;276:107051. doi: 10.1016/j.imlet.2025.107051. Epub 2025 Jun 7).
The instant application is drawn to the treatment of ILC2 mediated diseases comprising administration of a KLRG1 binding agent claim 1. In claim 2 the binding agent is an antibody or fragment thereof which binds the extra cellular domain of KLRG1. In claim 4 this antibody may be a full length antibody. Claims 6 and 8 are not further limiting over claim 1 as detailed in the 112(d) rejection above.
Greenberg teaches a method of treating metastatic breast cancer comprising administering an antibody or fragment thereof that disrupts KLRG1 signaling and activates CD8+ cytotoxic T and/or NK cells by binding an extracellular domain of a human protein selected from the group: KLRG1, E-cadherin, N-cadherin, and R-cadherin par.16 and claim 1. Greenberg teaches this method in a mouse breast cancer model using an anti-KLRG1 antibody, beginning in Par.294, Example 22.
It is noted that breast cancer is an ILC2 mediated disease as evidenced by Mojic p.4 in the paragraph labeled ILC2 in the breast cancer.
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, 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 2, 4, 6, 7, 11 are rejected under 35 U.S.C. 103 as being unpatentable over Hewitt et al. (WO-9854209-A2) as evidenced by Lehuen-Monteiro et al. (US 20190011432 A1).
Claim 1 is drawn to a method of treating an ILC2 mediated disease comprising administration of a KLRG1 or KLRG1 ligand binding agent.
Hewitt teaches a method of treatment for an inflammatory disease and also envisions the administration of effective doses of antibodies in this method. (p.8 par.6 and claim 19), one example of an inflammatory disease envisioned to be treated by the method of Hewitt is asthma (p.1, par.1), Hewitt teaches an antibody or fragment thereof specific for an epitope of the C terminal extracellular domain of human MAFA on p.8 par.1.
The antibody of Hewitt is the binding agent for KLRG1 in the instant application. Asthma is an ILC2 mediated disease as evidenced by instant specification par.45. It would have been obvious for a person having ordinary skill in the art wishing to treat an inflammatory disease such as asthma to use the anti-human-MAFA antibody disclosed above because Hewitt teaches that said antibody can be used in the treatment of inflammatory diseases which includes asthma in claims 8 and 19. A person having ordinary skill in the art would be motived to treat asthma to improve therapeutic outcomes and prevent death. It is noted that Lehuen-Monteiro, teaches that MAFA is the same as KLRG1, par.19.
In regards to claim 4 the antibody can be a full-length antibody as Hewitt contemplates both antibodies and fragments thereof p.8 and claim 11.
In regards to claim 6 and 7 are rejected as above as the antibody of Hewitt binds the extracellular domain of human MAFA / KLRG1.
Claims 3 is rejected under 35 U.S.C. 103 as being unpatentable over Hewitt as applied to claim 2 above, and further in view of Human Monoclonal Antibodies Methods and Protocols (2017 doi.org/10.1007/978-1-62703-586-6) hereinafter HMA.
As indicated above Hewitt teaches claim 2. Hewitt does not teach a human or humanized antibody as in claim 3.
HMA teaches humans are largely tolerant of the constant regions of their own antibodies (self tolerance) p.3 par. 1. It would have been obvious for a person having ordinary skill in the art to combine the methods of Hewitt with the teachings of HMA to reduce immunogenicity in human subjects by humanizing antibodies and one would have a reasonable expectation of success because HMA teaches humanized versions of rodent antibodies appeared far less immunogenic after a single course p.3 par.1.
Claims 5, 8, 9, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Hewitt as applied to claim 1 and 4 above, and further in view Greenberg in further view of Sedykh et al. (Bispecific antibodies: design, therapy, perspectives. Drug Des Devel Ther. 2018 Jan 22; 12:195-208. doi: 10.2147/DDDT.S151282).
In regards to claims 5, 8, 9 and 10. As indicated above Hewitt teaches claim 1 and 4. Hewitt does not teach a bispecific or trispecific antibody as in claim 5, a ligand binding agent as in claim 8, or that the ligand binding agent is a human cadherin as in claim 9. Hewitt does not specifically teach the binding agent binds at the KLRG1/cadherin binding site as in claim 10.
The general teachings of Greenberg are detailed in the 102 rejections above, it is important to point out Greenberg contemplated binding agents for KLRG1 and its ligands in claim 1 and teaches the binding agent binds at the KLRG1/cadherin binding site par.174, which pertains to claim 10. Greenberg also teaches they are human versions in par. 36 which pertains to the limitations of instant claim 9.
Sedykh teaches bispecific antibodies can provide higher binding specificity, since in contrast to monospecific antibodies, they interact with two different surface antigens and reduce costs compared to two monospecific antibodies. p.196 par. 3. It would have been obvious for a person having ordinary skill in the art to combine the teachings of Hewitt, Greenberg, and Sedykh to construct bispecific antibodies that target KLRG1 and its human cadherin ligands such as e-cadherin because Greenberg contemplates both of these antibodies in par. 22, and one would be motivated to use human versions for treatment of human subjects. A person having ordinary skill in the art would have a reasonable expectation of success because Sedykh teaches a multitude of bispecific antibodies have made it to clinical trials in Table 1 beginning on p.199, and a person having ordinary skill in the art would recognize that a binding agent at the binding site would be more likely to ensure a biological effect.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Hewitt as applied to claim 11 above, and further in view Li et al. (European Journal of Immunology 2019 from IDS filed 6/30/2023) in further view of Kim et al. (Innate lymphoid cells in asthma: Will they take your breath away?. Eur J Immunol. 2016 April; 46(4): 795–806. doi:10.1002/eji.201444557) in further view of Greenberg.
The teachings of Hewitt are detailed in the rejection of inter alia claim 11 above which include asthma generally. Hewitt does not specifically teach fungal or viral asthma from influenza A of claim 12.
Li teaches experiments in asthma, specifically models of influenza A and house dust mites (HDM) p.151 fig 5A. Li teaches an increase in inflammatory responses and epithelial damage of mouse lungs when exposed to influenza A (X31) and house dust mite (HDM) as compared to the unchallenged control fig.4E, and that ILC2 cells are increased over Naïve controls in fig.D (labeled ILC2). Li teaches IL-5 and IL-13 producing ILC2 cells fig 3A, these are type 2 cytokines as evidenced by Kim p.10 par.4. KLRG1 is also increased compared to naive control in Fig.3C. And mice lost weight in Fig.2A. Taken together these results implicate ILC2 cells when activated as proinflammatory cytokine producers.
Kim teaches inflammatory ILC2s (iILC2s) express high levels of KLRG1 in the lungs. Kim also teaches binding of KLRG1 to E-cadherin was shown to inhibit cytokine production and proliferation of ILC2s, Kim suggests that targeting ILC modulators such as KLRG1 could limit their pathologic potentials p.12 par.3.
It would have been obvious for a person having ordinary skill in the art to use the KLRG1 binding antibody method of Hewitt to target viral asthma from influenza A of Li because of the role of ILC2s and high KLRG1 as indicated above and Kim suggests targeting KLRG1. A person having ordinary skill in the art would be motivated because Li teaches influenza is able to cause the most severe forms of asthma p.144 introduction, and one would want to expand the types of asthma treated by the methods of Hewitt. One would have expected a high probability of success because Greenberg teaches successful use of antibodies in KLRG1 therapy in example 22 par. 295.
Claims 13 is rejected under 35 U.S.C. 103 as being unpatentable over Hewitt as applied to claims 1 and 11 above, in view of Klein Wolterink et al. (Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma, European Journal of Immunology 2012, DOI: 10.1002/eji.201142018) in further view of Kim in further view of Greenberg.
The teachings of Hewitt are detailed in the rejection of claims 1 and 11 above which include asthma generally. Hewitt does not specifically teach the allergic airway diseases of claim 13 including allergic inflammation from house dust mites.
Klein Wolterink teaches in house dust mite induced allergic asthma pulmonary ILC2s did not only increase in number, but concomitantly also the proportions of cytokine containing cells increased p.1110 right paragraph and Fig. Klein Wolterink teaches that ILC2s produce large amounts of IL-5 and IL-13 that contribute to allergic inflammation in asthma.
Kim teaches inflammatory ILC2s (iILC2s) express high levels of KLRG1 in the lungs. Kim also teaches binding of KLRG1 to E-cadherin was shown to inhibit cytokine production and proliferation of ILC2s, Kim suggests that targeting ILC modulators such as KLRG1 could limit their pathologic potentials p.12 par.3.
It would have been obvious for a person having ordinary skill in the art to combine the anti-KLRG1 antibody methods of Hewitt with the teachings Klein Wolterink of high ILC2s and cytokines in house dust mite allergic models to treat house dust mite allergic airway disease because a person having ordinary skill in the art would have been motivated to prevent allergic inflammation in asthma by inhibiting ILC2 cells from producing IL-5 and IL-13. One would have expected a high probability of success because Greenberg teaches successful use of antibodies in KLRG1 therapy in example 22 par. 295.
Conclusion
No claims are allowed.
Inquiry Information
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/RUDOLPH E. SLOUP Jr. IV Ph.D./
Examiner, Art Unit 1645
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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