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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/23/2025 has been entered.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1,3-5, 7, 9-11, 13, 15, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (US20100158898A1, of record), hereinafter Liu, in view of Sahin et al (US20100111975A1, of record), hereinafter Sahin, and Bruhns et al (Bruhns, Pierre, and Friederike Jönsson. "Mouse and human FcR effector functions." Immunological reviews 268.1 (2015): 25-51, of record), hereinafter Bruhns.
Liu discloses methods for the treatment or prophylaxis an IgE-mediated disorder in a subject comprising administering of a highly concentrated anti-IgE antibody formulation to the subject, wherein the anti-IgE antibody is rhuMAbE25 (omalizumab, see OA.Appendix, of record) and the IgE-associated disorder is, for example, asthma, urticaria, or IgE myeloma (see entire document, in particular, Abstract, Summary of the Invention, Claims, Section E: Methods of Treatment, Section H: Administration of the Formulation, Para. 0016-0017, and Para. 0089-0091). The anti-IgE antibody of the instant claims comprises the variable regions- VH and VL chains- of omalizumab as well as its constant light chain. As such, the claimed light chain SEQ ID NO: 6 corresponds to the light chain of omalizumab; and the claimed heavy chain of SEQ ID NO: 3 fully comprises the VH region of omalizumab. Thus, the anti-IgE antibody of the instant claims differs from that of omalizumab in the type of heavy chain constant region (CH) (residues 122-447) and in the presence of LALA or N297A mutations. The heavy and light chains of omalizumab provided by DrugBank is provided below [the variable -VH and VL- regions are in bold and the constant regions -CH and CL- are underlined) (DrugBank Online ID: DB00043, shown below, first created on June 13, 2005 and deposited in/computed by PubChem on January 17, 2008. OA.Appendix, of record).
>Omalizumab heavy chain
EVQLVESGGGLVQPGGSLRLSCAVSGYSITSGYSWNWIRQAPGKGLEWVASITYDGSTNY
ADSVKGRFTISRDDSKNTFYLQMNSLRAEDTAVYYCARGSHYFGHWHFAVWGQGTLVTVS
SGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK
>Omalizumab light chain
DIQLTQSPSSLSASVGDRVTITCRASQSVDYDGDSYMNWYQQKPGKAPKLLIYAASYLES
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHEDPYTFGQGTKVEIKRTVAAPSVF
IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS
STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR
Liu does not specifically teach that 1) the subject has serum IgE levels equal to or higher than 700 IU/mL and is in need of an anti-human IgE antibody alternative to omalizumab or 2) that the has a heavy chain constant region set forth in SEQ ID NO: 3, wherein the heavy chain further comprises at least one Fc mutation selected from 1) LALA (L234A/L235A) or 2) N297A, which yields an Fc region defined by SEQ ID NO: 4 or 5.
However, Pelaia teaches that utilization of omalizumab is approved for patients with total plasma IgE levels ranging from 30 to 1500 IU/mL in the European Union (“Practical use and overview of clinical studies” section). Further, while omalizumab is generally well-tolerated anaphylactic reactions in some patients have been reported (1st paragraph under “Safety” section), highlighting the need for some patients of an omalizumab alternative that does not induce anaphylaxis.
Sahin further teaches that a heavy chain constant region (CH) that can be used in a therapeutic antibody, wherein the CH chain has an amino acid sequence represented by SEQ ID NO: 24, corresponding to the heavy constant chain region (residues 122-447) of SEQ ID NO: 3 of the instant claims (see entire document, in particular, Para. 0064).
Bruhns further teaches that abrogating effector functions of antibodies via Fc mutations that affect the affinity and specificity of IgG-FcyR interactions is a necessity to prevent adverse reactions including anaphylaxis. The N297A (NA) and the L234A/L235A ( LALA) mutations abrogate binding to all human FyRs and strongly reduce/abrogate the binding to human C1q. As such, these ADCC, ADP, and CDC effector functions of IgG1 LALA or IgG1 N297A antibodies are abrogated. These IgG1 variants thus represent prototypic mutations for antibodies without any effector function in vivo (see entire document, in particular, “IgG Fc mutations that affect IgG-FcyR interactions” and “Outstanding IgG1 Variants” sections as well as Table 5). Thus, N297A and LALA mutations in IgG1 are reasonably expected to reduce and/or prevent adverse reactions, including anaphylaxis.
It would have been obvious to one of ordinary skill in the art to modify the method of treating an IgE-associated disorder in a subject disclosed by Liu such that 1) the subject has serum IgE levels ≥ 700 IU/mL and requires an anti-IgE alternative to omalizumab and 2) the anti-IgE antibody omalizumab is modified to comprise the heavy constant chain of SEQ ID NO: 3 and the Fc mutations L234A/L235A (LALA) or N297A, thereby yielding an Fc region defined by SEQ ID NO: 4 or 5. One of ordinary skill in the art would have been motivated to do so because although omalizumab can be administered to patients with plasma IgE levels up to 1500 IU/mL in the European Union, there remains a risk of anaphylaxis in some patients as taught by Pelaia. Smith teaches that the heavy chain constant region of SEQ ID NO 24 is suitable for therapeutic antibodies, making it an obvious alternative to the constant region of omalizumab (or residues 122-447 of SEQ ID NO: 3). Further, introducing the LALA and N297A mutations in IgG1 reduce effector functions, including anaphylaxis as taught by Bruhns. Lastly, the minimal structure required for an “anti-IgE antibody alterative to omalizumab” to not activate and/or induce degranulation of neutrophils, mast cells or basophils is a heavy chain of SEQ ID NO: 3 and a light chain of SEQ ID NO: 6, wherein the heavy chain further comprises LALA or N297A mutations. The combined teachings of the prior art render obvious the anti-IgE antibody alternative which would necessarily have the properties of not activating and/or inducing degranulation of neutrophils, mast cells, and basophils. Therefore, one of ordinary skill in the art would expect an anti-IgE antibody omalizumab modified to comprise the heavy constant chain of SEQ ID NO: 3 and the Fc mutations LALA and N297A to more safely and effectively treat IgE-mediated disorders in a subject having serum IgE levels ≥ 700 IU and in need of an anti-IgE alternative to omalizumab.
Claims 2, 8, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Pelaia, Sahin, and Bruhns, as applied to claims 1,3-5, 7, 9-11, 13, 15, and 16 above, and further in view of Maurer et al (Maurer, Marcus, et al. "Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria." New England Journal of Medicine 368.10 (2013): 924-935, of record), hereinafter Maurer.
The teachings of Liu in view of Pelaia, Sahin, and Bruhns have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the IgE-associated disorder urticaria is chronic idiopathic urticaria.
However, Maurer discloses that many patients with chronic idiopathic urticaria (itchy hives that last for at least 6 weeks and that have no apparent external trigger) do not have a response to therapy with H1-antihistamines, even at high dose. In phase 3 clinical trials, though, anti-IgE therapy diminishes clinical symptoms and signs of chronic idiopathic urticaria in patients who had remained symptomatic despite the use of approved doses of H1-antihistamines (see entire document, in particular, Abstract and Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating an IgE associated disorder in a subject with anti-IgE antibodies disclosed by Liu in view of Pelaia, Sahin, and Bruhns such that the IgE-associated disorder is chronic idiopathic urticaria. One of ordinary skill in the art would have been motivated to do so since anti-IgE therapy is capable of diminishing clinical symptoms and signs of chronic idiopathic urticaria in patients who had remained symptomatic despite the use of approved doses of H1-antihistamines. Therefore, one of ordinary skill in the art would expect that the method of treating an IgE-associated disorder disclosed by Liu in view of Pelaia, Sahin, and Bruhns can be used to effectively treat patients having chronic idiopathic urticaria.
Claims 6, 12, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Pelaia, Sahin, and Bruhns, as applied to claims 1,3-5, 7, 9-11, 13, 15, and 16 above, and further in view of Neugut et al (Neugut, Alfred I., Anita T. Ghatak, and Rachel L. Miller. "Anaphylaxis in the United States: an investigation into its epidemiology." Archives of internal medicine 161.1 (2001): 15-21, of record), hereinafter Neugut.
The teachings of Liu in view of Pelaia, Sahin, Bruhns have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the subject has a history of anaphylaxis.
However, Neugut teaches that individuals who have had previous anaphylactic reactions can be at risk of future anaphylactic reactions, and the most effective and reliable method of identifying individuals at risk of anaphylaxis is through a documented history of previous anaphylactic episodes (see Abstract, Introduction, and Mechanisms section).
It would have been obvious to one of ordinary skill in the art to modify the method of treating IgE-associated disorders in a subject disclosed by Liu in view of Pelaia, Sahin, Bruhns such that the subject has a history of anaphylaxis. One of ordinary skill in the art would have been motivated to do so since subjects having a history of anaphylaxis have an increased risk of future anaphylactic reactions; and the method of treating IgE-associated disorders in a subject comprising administering anti-IgE antibodies disclosed by Liu in view of Pelaia, Sahin, and Bruhns can be used to effectively inhibit or reduce the risk of anaphylaxis. Therefore, one of ordinary skill in the art would expect that the method of treating IgE-associated disorders in a disclosed by Liu in view of Pelaia, Sahin, and Bruhns can be used to effectively inhibit or reduce the risk of anaphylaxis in a subject has a history of anaphylaxis.
Response to Arguments
Applicant’s arguments filed 12/05/2024 with respect to the rejection of claims under 35 U.S. C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Liu et al.
With respect to the rejections made under 35 U.S.C. 103, Applicant argues the following:
Sahin teaches antibodies that bind to GT468 expressed on cells to treat tumor-related diseases by killing and/or inhibiting one or more activities of cancer cells via effector functions such as ADCC and CDC. None of these effects, activities, or cell types are required or involved in the method of the claimed invention.
Bruhns teaches that N297A and LALA mutations abrogate binding to FcRs and human C1q, thus abrogating effector functions. However, again, none of these effector functions are required or involved in the effector functions in the method of the claimed invention.
The combined teachings of the prior art -Liu, Sahin, and Bruhns- do not teach any type of caution regarding high levels of IgE and fails to provide an alternative to omalizumab. Omalizumab has been associated with adverse reactions ranging from skin inflammation to anaphylaxis, and the FDA has restricted the use of omalizumab to patients with severe asthma and serum IgE levels below 700 IU/mL. Accordingly, there is a need for anti-IgE antibody alternatives to omalizumab that are safer and effective.
Belliveau teaches that anaphylaxis in response to omalizumab is rare and resolved quickly whether or not treatment with the anti-IgE antibody was continued or discontinued, and thus minimized the need for an alternative to omalizumab.
Maurer does not teach IgE titers or identification of any patients who should be excluded from the study due to high IgE levels or a history of anaphylaxis and these patients represent a distinct population that would now be excluded from receiving omalizumab under FDA guidelines.
Neugut discloses that subjects with a history of anaphylaxis are at higher risk of anaphylaxis and thus artisans would be even less motivated to modify the method of Liu.
In response to Applicant’s arguments, the Examiner notes that Pelaia teaches that omalizumab is approved for patients with total plasma IgE levels up to 1500 IU/mL in the European Union and is generally well-tolerated, yet anaphylactic reactions in some patients do occur albeit rarely. Even though anaphylaxis is not a common response to omalizumab treatment, it can be life-threatening, highlighting a patient population that would require an alternative to omalizumab. Liu teaches methods of treating an IgE-mediated disorder such as asthma, urticaria, or IgE myeloma, comprising administering anti-IgE antibody omalizumab. The anti-IgE antibody omalizumab of Liu differs from that of the instant claims in the type of heavy chain constant region (CH) (residues 122-447) and in the presence of LALA or N297A mutations. However, Smith teaches that the heavy chain constant region of SEQ ID NO 24 (corresponding to residues 122-447 of SEQ ID NO: 3) is suitable for therapeutic antibodies, making it an obvious alternative to the constant region of omalizumab. Sahin is not relied upon for the teachings of anti-cancer antibodies specifically. Bruhns further teaches that the LALA or N297A mutations in human IgG1 antibodies have been shown to reduce FcγR and C1q binding and thus undesired ADCC and CDC effector functions, including anaphylaxis. Further, introducing the LALA and N297A mutations in IgG1 reduce effector functions, including anaphylaxis as taught by Bruhns. Lastly, the minimal structure required for an “anti-IgE antibody alterative to omalizumab” to not activate and/or induce degranulation of neutrophils, mast cells or basophils is a heavy chain of SEQ ID NO: 3 and a light chain of SEQ ID NO: 6, wherein the heavy chain further comprises LALA or N297A mutations. The combined teachings of the prior art render obvious the anti-IgE antibody alternative which would necessarily have the properties of not activating and/or inducing degranulation of neutrophils, mast cells, and basophils. Therefore, one of ordinary skill in the art would expect an anti-IgE antibody omalizumab modified to comprise the heavy constant chain of SEQ ID NO: 3 and the Fc mutations LALA and N297A to more safely and effectively treat IgE-mediated disorders in a subject having serum IgE levels ≥ 700 IU and in need of an anti-IgE alternative to omalizumab.
Further, Belliveau is not relied upon in any of the rejections in the present Office Action. Maurer highlights a patient population – chronic idiopathic urticaria- that would receive therapeutic benefit from anti-IgE therapy regardless of current FDA guidelines. Thus, artisans would have been motivated to administer the modified omalizumab taught by Liu in view of Pelaia, Bruhns, and Sahin in order to treat patients having chronic idiopathic urticaria. Lastly, Neugut discloses that subjects with a history of anaphylaxis are at higher risk of anaphylaxis. Given that omalizumab can in rare cases cause anaphylactic reactions, artisans would be motivated to administer the modified the modified omalizumab taught by the combined teachings of the prior art which can reduce or inhibit anaphylaxis to a patient having an IgE-mediated disorder and history of anaphylaxis.
Thus, the rejections over 35 USC 103 are maintained.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641