Office Action 1: Non-Final Rejection (2024-08-08)
Rejection types: 112 - Written Description/Enablement

CLAIMS:
CLAIMS

What is claimed is:

1\. A method of treating an IL1 RAP mediated disease in a subject, comprising administering to the subject a therapeutically effective amount of an antibody, wherein the antibody comprises: (i) a first light chain hypervariable region (HVR-L1), a second light chain hypervariable region (HVR-L2), and a third light chain hypervariable region (HVR-L3), and (ii) a first heavy chain hypervariable region (HVR-H1), a second heavy chain hypervariable region (HVR-H2), and a third heavy chain hypervariable region (HVR-H3); wherein:
(a) HVR-L1 comprises an amino acid sequence of SEQ ID NO: 11;
(b) HVR-L2 comprises an amino acid sequence selected from SEQ ID NO: 37, and 54;
(c) HVR-L3 comprises an amino acid sequence selected from SEQ ID NO: 63, 69, and
70;
(d) HVR-H1 comprises an amino acid sequence of SEQ ID NO: 78;
(e) HVR-H2 comprises an amino acid sequence selected from SEQ ID NO: 191, and
195;
(f) HVR-H3 comprises an amino acid sequence selected from SEQ ID NO: 203 and 215.

2\. The method of claim 1, wherein the antibody comprises:
a first light chain framework region (FR-L1) comprising an amino acid sequence of SEQ ID NO: 244;
a second light chain framework region (FR-L2) comprising an amino acid sequence of SEQ ID NO: 246;
a third light chain framework region (FR-L3) comprising an amino acid sequence of SEQ ID NO: 247; and
a fourth light chain framework region (FR-L4) comprising an amino acid sequence of SEQ ID NO: 248; or
a first heavy chain framework region (FR-H1) comprising an amino acid sequence of SEQ ID NO: 253;
a second heavy chain framework region (FR-H2) comprising an amino acid sequence of SEQ ID NO: 254;
a third heavy chain framework region (FR-H3) comprising an amino acid sequence of SEQ ID NO: 255; and a fourth heavy chain framework region (FR-H4) comprising an amino acid of SEQ ID NO: 256.

3\. The method of claim 1, wherein the antibody comprises a light chain variable domain (VL) amino acid sequence having at least 90% identity to SEQ ID NO: 259; and/or a heavy chain variable domain (VH) amino acid sequence having at least 90% identity to SEQ ID NO:
290.

4\. The method of claim 3, wherein the antibody comprises:
the light chain variable domain (VL) amino acid sequence of SEQ ID NO: 259, and the heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 290;
the light chain variable domain (VL) amino acid sequence of SEQ ID NO: 268, and the heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 307;
the light chain variable domain (VL) amino acid sequence of SEQ ID NO: 268, and the heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 298;
the light chain variable domain (VL) amino acid sequence of SEQ ID NO: 269, and the heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 307;
the light chain variable domain (VL) amino acid sequence of SEQ ID NO: 269, and the heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 298;
the light chain variable domain (VL) amino acid sequence of SEQ ID NO: 269, and the heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 297;
the light chain variable domain (VL) amino acid sequence of SEQ ID NO: 270, and the heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 307; or
the light chain variable domain (VL) amino acid sequence of SEQ ID NO: 270, and the heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 298.

5\. The method of claim 1, wherein the antibody comprises a light chain (LC) amino acid sequence having at least 90% identity to SEQ ID NO: 328; and/or a heavy chain (HC) amino acid sequence having at least 90% identity to SEQ ID NO: 332.

6\. The method of claim 5, wherein the antibody comprises:
the light chain (LC) amino acid sequence of SEQ ID NO: 328, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 332;
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 335;
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 336;
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 333;
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 334;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 335;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 336;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 333;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 334;
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 335;
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 336;
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 333; or
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 334.

7\. The method of claim 1, wherein an IL-1 stimulated signal, an IL-33 stimulated signal, or
an IL-36 stimulated signal in the subject is decreased by at least 90%.

8\. The method of claim 1, wherein an intracellular signal initiated by one or more of IL-1 a, IL-1 p, IL-33, IL-36a, IL-36p, and IL-36y agonist binding to its cognate receptor in the subject is decreased by at least 90%.

9\. The method of claim 1, wherein the antibody specifically binds to one or more amino acid residues within domain 3 of human IL1 RAP, wherein domain 3 comprises positions 238 - 367 of the amino acid sequence of SEQ ID NO: 1 or 3.

10\. The method of claim 1, wherein the antibody does not bind to amino acid residues within domain 1 or domain 2 of human IL1 RAP; optionally, wherein domain 1 and domain 2 comprise positions 21 - 237 of the amino acid sequence of SEQ ID NO: 1 or 3.

11\. The method of claim 1, The antibody of claim 1, wherein the antibody cross-reacts with a cynomolgus monkey IL1 RAP polypeptide of SEQ ID NO: 8.

12\. The method of claim 1, wherein the antibody is a full-length antibody of class IgG;
optionally, wherein the class IgG antibody has an isotype selected from IgG1, IgG2, IgG3, and
IgG4.

13\. The method of claim 1, wherein the antibody is an Fc region variant; optionally wherein the Fc region variant alters effector function or alters half-life.

14\. The method of claim 13, wherein the Fc region variant comprises a set of YTE mutations.

15\. The method of claim 13, wherein the Fc region variant decreases effector function.

16\. The method of claim 1, wherein the antibody is formulated in a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier.
17\. The method of claim 1, wherein the IL1 RAP mediated disease is selected from the group consisting of: acne, acute pancreatitis, acute severe ulcerative colitis, adult-onset Still's disease, age-related macular degeneration (AMD), airway hyperresponsiveness, airway inflammation, allergic conjunctivitis, allergic rhinitis, allergy, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), anaphylaxis, arthritis pain, asthma, atherosclerosis, atopic dermatitis, atopic eczema, autoimmune vasculitis, Behcet's disease, bone cancer, brain cancer, breast cancer, cachexia/anorexia, cartilage damage, cerebral ischemia, chronic fatigue syndrome, chronic obstructive pulmonary disease, Clostridium associated illnesses, colon cancer, congestive heart failure, conjunctivitis, coronary artery bypass graft, coronary restenosis, Crohn's disease, diabetes, diabetic macular edema, diabetic retinopathy, dry eye disease, endometriosis, eosinophil-associated gastrointestinal disorder, eosinophilic esophagitis, familial cold autoinflammatory syndrome, familial Mediterranean fever, fever, fibromyalgia, fibrotic disorder, food allergy, generalized pustular psoriasis, glaucoma, glomerulonephritis, gouty arthritis, graft versus host disease, helminth infection, hemorrhagic shock, hidradenitis suppurativa, hyperalgesia, hyper-IgD syndrome, hyperuricemia, idiopathic pulmonary fibrosis (IPF), cancer-related pain, infection, inflammatory bowel disease (IBD), inflammatory conditions resulting from strain, inflammatory eye disease associated with corneal transplant, inflammatory pain, influenza, intestinal cancer, ischemia, juvenile arthritis, Kawasaki's disease, kidney cancer, Leber's congenital amaurosis, liver cancer, liver disease, lung cancer, Muckle-Wells syndrome, multiple myeloma, multiple sclerosis, musculoskeletal pain, myelogenous and other leukemias, myocardial dysfunction, myopathies, nasal polyp, neonatal onset multisystem inflammatory disease, neurotoxicity, non-infectious conjunctivitis, non-small cell lung cancer, orthopedic surgery, osteoarthritis, osteoporosis, pain, palmoplantar pustulosis, pancreas cancer, Parkinson's disease, periodontal disease, peripheral vascular disease, polymyalgia rheumatica, polypoidal choroidal vasculopathy (PCV), pre-term labor, prostate cancer, protozoan infection, psoriasis, psoriatic arthritis, pyoderma gangrenosum, reperfusion injury, respiratory syncytial virus (RSV), restenosis, retinal detachment, retinitis pigmentosa, retinopathy of prematurity (ROP), rheumatoid arthritis, septic shock, sickle-cell anemia, side effects from radiation therapy, sinusitis, skin cancer, sleep disturbance, sprain, Stargardt's disease, stomach cancer, temporal mandibular joint disease, TNF receptor associated periodic syndrome, transplant rejection, trauma, traumatic eye injury, type-2 diabetes, ulcerative colitis, and uveitis.

18\. The method of claim 1, further comprising administering to the subject a second therapeutic agent that prevents or treats an IL1 RAP mediated disease.

19\. The method of claim 1, wherein the antibody is administered systemically.

20\. The method of claim 1, wherein the antibody is administered at a dose of from about 1 pg/kg to about 15 mg/kg.

21\. The method of claim 1, wherein the method further comprises administering to the subject a dose of up to about 100 mg/kg. - 127 - - 128 - - 129 - -130 - -131 -

OFFICE ACTION:
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 claims
Claims 1-21 are pending and are examined.
Information Disclosure Statement
The information disclosure statements (IDS)s submitted on 09/27/2021 and 04/24/2024 were considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement.  37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, the list may not be incorporated into the specification but must be submitted in a separate paper.  Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
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.
Claims 1-21 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the  inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)).  To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).  See also MPEP 2163.04.
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69).  A “representative number of species” means that those species that are adequately described are representative of the entire genus.  AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
In the instant case, the claims are drawn to a genus of methods of treatment of IL1RAP mediated diseases. The diseases claimed comprise: acne, acute pancreatitis, acute severe ulcerative colitis, adult-onset Still's disease, age-related macular degeneration (MJID), airway hyperresponsiveness, airway inflammation, allergic conjunctivitis, allergic rhinitis, allergy, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), anaphylaxis, arthritis pain, asthma, atherosclerosis, atopic dermatitis, atopic eczema, autoimmune vasculitis, Behcet's disease, bone cancer, brain cancer, breast cancer, cachexia/anorexia, cartilage damage, cerebral ischemia, chronic fatigue syndrome, chronic obstructive pulmonary disease, Clostridium associated illnesses, colon cancer, congestive heart failure, conjunctivitis, coronary artery bypass graft, coronary restenosis, Crohn's disease, diabetes, diabetic macular edema, diabetic retinopathy, dry eye disease, endometriosis, eosinophil-associated gastrointestinal disorder, eosinophilic esophagitis, familial cold autoinflammatory syndrome, familial Mediterranean fever, fever, fibromyalgia, fibrotic disorder, food allergy, generalized pustular psoriasis, glaucoma, glomerulonephritis, gouty arthritis, graft versus host disease, helminth infection, hemorrhagic shock, hidradenitis suppurativa, hyperalgesia, hyper-lgD syndrome, hyperuricemia, idiopathic pulmonary fibrosis (IPF), cancer-related pain, infection, inflammatory bowel disease (I8D), inflammatory conditions resulting from strain, inflammatory eye disease associated with corneal transplant, inflammatory pain, influenza, intestinal cancer, ischemia, juvenile arthritis, Kawasaki's disease, kidney cancer, Leber’s congenital amaurosis, liver cancer, liver disease, lung cancer, Muckle-Wells syndrome, multiple myeloma, multiple sclerosis, musculoskeletal pain, myelogenous and other leukemias, myocardial dysfunction, myopathies, nasal polyp, neonatal onset multisystem inflammatory disease, neurotoxicity, non-infectious conjunctivitis, non-small cell lung cancer, orthopedic surgery, osteoarthritis, osteoporosis, pain, palmoplantar pustulosis, pancreas cancer, Parkinson's disease, periodontal disease, peripheral vascular disease, polymyalgia rheumatica, polypoidal choroidal vasculopathy (PCV), pre-term labor, prostate cancer, protozoan infection, psoriasis, psoriatic arthritis, pyoderma gangrenosum, reperfusion injury, respiratory syncytial virus (RSV), restenosis, retinal detachment, retinitis pigmentosa, retinopathy of prematurity (ROP), rheumatoid arthritis, septic shock, sickle-cell anemia, side effects from radiation therapy, sinusitis, skin cancer, sleep disturbance, sprain, Stargardt's disease, stomach cancer, temporal mandibular joint disease, TNF receptor associated periodic syndrome, transplant rejection, trauma, traumatic eye injury, type-2 diabetes, ulcerative colitis, and uveitis. This extensive menu of diseases claimed to be treated are not backed by any data showing even a bare bones method (administration regimen, dose, length of treatment and metrics for assessing the efficacy of the treatment). There is no indication that any of the diseases claimed were treated. The only method that Applicant is in possession of is an in vitro method of blocking IL1RAP activity with antibody 14F4 (example 17) and an in vivo method of blocking complex phenotypes induced in mouse models of asthma ([0490]).
Given the complexity of the diseases claimed and the lack of guidance and working examples, a person of ordinary skill in the art would conclude that the genus of methods claimed were not in Applicant’s possession. In the best case scenario, Applicant may be in possession of a method of treating asthma with the antibodies claimed.
Claims 1-21 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 treating asthma with the antibodies claimed in the independent claim 1, does not reasonably provide enablement for treating all diseases IL1RaP mediated diseases.  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.
The claims are drawn to a genus of methods of treatment of IL1RAP mediated diseases. The diseases claimed comprise acne, acute pancreatitis, acute severe ulcerative colitis, adult-onset Still's disease, age-related macular degeneration (MJID), airway hyperresponsiveness, airway inflammation, allergic conjunctivitis, allergic rhinitis, allergy, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), anaphylaxis, arthritis pain, asthma, atherosclerosis, atopic dermatitis, atopic eczema, autoimmune vasculitis, Behcet's disease, bone cancer, brain cancer, breast cancer, cachexia/anorexia, cartilage damage, cerebral ischemia, chronic fatigue syndrome, chronic obstructive pulmonary disease, Clostridium associated illnesses, colon cancer, congestive heart failure, conjunctivitis, coronary artery bypass graft, coronary restenosis, Crohn's disease, diabetes, diabetic macular edema, diabetic retinopathy, dry eye disease, endometriosis, eosinophil-associated gastrointestinal disorder, eosinophilic esophagitis, familial cold autoinflammatory syndrome, familial Mediterranean fever, fever, fibromyalgia, fibrotic disorder, food allergy, generalized pustular psoriasis, glaucoma, glomerulonephritis, gouty arthritis, graft versus host disease, helminth infection, hemorrhagic shock, hidradenitis suppurativa, hyperalgesia, hyper-lgD syndrome, hyperuricemia, idiopathic pulmonary fibrosis (IPF), cancer-related pain, infection, inflammatory bowel disease (I8D), inflammatory conditions resulting from strain, inflammatory eye disease associated with corneal transplant, inflammatory pain, influenza, intestinal cancer, ischemia, juvenile arthritis, Kawasaki's disease, kidney cancer, Leber’s congenital amaurosis, liver cancer, liver disease, lung cancer, Muckle-Wells syndrome, multiple myeloma, multiple sclerosis, musculoskeletal pain, myelogenous and other leukemias, myocardial dysfunction, myopathies, nasal polyp, neonatal onset multisystern inflammatory disease, neurotoxicity, non-infectious conjunctivitis, non-small cell lung cancer, orthopedic surgery, osteoarthritis, osteoporosis, pain, palmoplantar pustulosis, pancreas cancer, Parkinson's disease, periodontal disease, peripheral vascular disease, polymyalgia rheumatica, polypoidal choroidal vasculopathy (PCV), pre-term labor, prostate cancer, protozoan infection, psoriasis, psoriatic arthritis, pyoderma gangrenosum, reperfusion injury, respiratory syncytial virus (RSV), restenosis, retinal detachment, retinitis pigmentosa, retinopathy of prematurity (ROP), rheumatoid arthritis, septic shock, sickle-cell anemia, side effects from radiation therapy, sinusitis, skin cancer, sleep disturbance, sprain, Stargardt's disease, stomach cancer, temporal mandibular joint disease, TNF receptor associated periodic syndrome, transplant rejection, trauma, traumatic eye injury, type-2 diabetes, ulcerative colitis, and uveitis.
For this extensive menu of diseases, which have different etiologies and largely different methods of treatment, Applicant does not present any experimental data for in vivo treatment. The only method that could somehow come closer to the blue print for a method of treatment is an in vivo method of blocking complex phenotypes induced in mouse models of asthma with the antibody 14F4 ([0490]).
The art is aware of method of treatment for leukemias and solid tumor selected from prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer, and sarcomas (Ågerstam et al., U.S. Pat. No. 10,100,119; Fioretos et al., U.S. Pat. No. 9,403,906, all cited by Applicant)  as well as Hidradenitis Suppurativa (Fischer et al., U.S. Pat. No.11, 639,392). However, for the diseases shown to be treated, the structure of the antibodies used is different from the structure of the antibody claimed in the instant Application. Each antibody to be used in vivo needs to be thoroughly tested in order to assess its, potential therapeutical value and the testing methods are cumbersome  and time consuming, with no a priori knowledge of their efficacy. Such an amount of experimentation is, in view of the extremely limited guidance and working examples, considered to be undue.
Thus the only method considered enabled is the method of treating asthma with the antibodies claimed in the independent claim 1.
Conclusion
No claims are allowed.

APPLICANT REBUTTAL: REMARKS
Status of the Claims
With entry of the above-listed amendments:
Claims 17-18 are Canceled.
Claim 1 is Currently Amended.
Claims 1-16 and 19-21 are Pending.
Amendments
In the Claims
Claim 1 has been amended as shown in the above listing to limit the IL1-mediated
disease to asthma. Support for this amendment is found in original claim 17 and throughout the specification.
No new matter is added by the amendments.
Applicant Comments
/Arg
uments Regarding Pendin
g
Ob
j
ections
/Rej
ections
Claim Rejections - 35 USC § 112
Claims 1-21 are rejected under 35 USC § 112 for allegedly failing to comply with the
written description requirement. In order to expedite prosecution and without acknowledging the propriety of the rejection, Applicant has amended the base independent claim to limit the recited IL1 RAP mediated disease to asthma as suggested by the Examiner. In view of this amendment, Applicant respectfully requests that the rejection for lack of written description under 35 USC § 112 be withdrawn.
Claims 1-21 are also rejected under 35 USC § 112 for allegedly failing to comply with the enablement requirement. In order to expedite prosecution and without acknowledging the propriety of the rejection, Applicant has amended the base independent claim to limit the recited IL1 RAP mediated disease to asthma as suggested by the Examiner. In view of this amendment, Applicant respectfully requests that the rejection for lack of enablement under 35 USC § 112 be withdrawn.
Conclusions

NEXT OFFICE ACTION: EXAMINER'S AMENDMENT
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 .
An examiner’s amendment to the record appears below. Should the changes and/or additions be unacceptable to applicant, an amendment may be filed as provided by 37 CFR 1.312. To ensure consideration of such an amendment, it MUST be submitted no later than the payment of the issue fee.
The application has been amended as follows:
In the title, please replace the current title with the following title:
-- Method of treating asthma with anti-IL1RAP antibodies --.
The allowed claims are: 1-16 and 19-21.
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance: Applicant amended the claims and thus remove the reasons for the rejection.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”

CITED REFERENCE SUMMARIES: Ref US11639392B2: Claims:
A method for treating an IL1R3-mediated inflammatory condition and/or disorder in a subject, comprising administering to the subject an antibody, or antigen binding fragment thereof, that specifically binds IL-1R3, wherein the antibody or antigen binding fragment comprises: a) a heavy chain variable region (VH) comprising the complementarity determining regions comprising CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1 region comprises an amino acid sequence set forth in SEQ ID NO: 79, wherein the CDR-H2 region comprises an amino acid sequence set forth in SEQ ID NO: 96, and wherein the CDR-H3 region comprises an amino acid sequence set forth in SEQ ID NO: 113; and b) a light chain variable region (VL) comprising the complementarity determining regions comprising CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1 region comprises an amino acid sequence set forth in SEQ ID NO: 130, wherein the CDR-L2 region comprises an amino acid sequence set forth in SEQ ID NO: 147, and wherein the CDR-L3 region comprises an amino acid sequence set forth in SEQ ID NO: 175, thereby treating the IL1R3-mediated inflammatory condition and/or disorder in the subject.
wherein the antibody or antigen binding fragment comprises: a) a heavy chain variable region (VH) comprising the complementarity determining regions comprising CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1 region comprises an amino acid sequence set forth in SEQ ID NO: 79, wherein the CDR-H2 region comprises an amino acid sequence set forth in SEQ ID NO: 96, and wherein the CDR-H3 region comprises an amino acid sequence set forth in SEQ ID NO: 113; and b) a light chain variable region (VL) comprising the complementarity determining regions comprising CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1 region comprises an amino acid sequence set forth in SEQ ID NO: 130, wherein the CDR-L2 region comprises an amino acid sequence set forth in SEQ ID NO: 147, and wherein the CDR-L3 region comprises an amino acid sequence set forth in SEQ ID NO: 175,
a) a heavy chain variable region (VH) comprising the complementarity determining regions comprising CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-H1 region comprises an amino acid sequence set forth in SEQ ID NO: 79, wherein the CDR-H2 region comprises an amino acid sequence set forth in SEQ ID NO: 96, and wherein the CDR-H3 region comprises an amino acid sequence set forth in SEQ ID NO: 113; and
wherein the CDR-H1 region comprises an amino acid sequence set forth in SEQ ID NO: 79,
wherein the CDR-H2 region comprises an amino acid sequence set forth in SEQ ID NO: 96,
and wherein the CDR-H3 region comprises an amino acid sequence set forth in SEQ ID NO: 113; and
b) a light chain variable region (VL) comprising the complementarity determining regions comprising CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-L1 region comprises an amino acid sequence set forth in SEQ ID NO: 130, wherein the CDR-L2 region comprises an amino acid sequence set forth in SEQ ID NO: 147, and wherein the CDR-L3 region comprises an amino acid sequence set forth in SEQ ID NO: 175,
wherein the CDR-L1 region comprises an amino acid sequence set forth in SEQ ID NO: 130,
wherein the CDR-L2 region comprises an amino acid sequence set forth in SEQ ID NO: 147, and
wherein the CDR-L3 region comprises an amino acid sequence set forth in SEQ ID NO: 175,
thereby treating the IL1R3-mediated inflammatory condition and/or disorder in the subject.
The method of claim 1 , wherein the VH region comprises an amino acid sequence set forth in SEQ ID NO: 28, and the VL region comprises an amino acid sequence set forth in SEQ ID NO: 174.
The method of claim 1 , wherein the antibody comprises a human IgG1 Fc region comprising at least amino acid substitutions at L234A and L235A of the human IgG1 Fc region, wherein the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system.
The method of claim 1 , wherein the antibody comprises a human IgG4 Fc region comprising at least amino acid substitutions at S228P and L235E of the human IgG4 Fc region, wherein the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system.
The method of claim 1 , wherein the IL1R3-mediated inflammatory condition and/or disorder is Hidradenitis Suppurativa.
A method for treating an IL1R3-mediated inflammatory condition and/or disorder in a subject, comprising administering to the subject an antibody, or antigen binding fragment thereof, that specifically binds IL-1R3, wherein the antibody or antigen binding fragment comprises: a) a VH region comprising an amino acid sequence set forth in SEQ ID NO: 28; b) a VL region comprising an amino acid sequence set forth in SEQ ID NO: 174; and c) a human IgG1 Fc region comprising at least amino acid substitutions at L234A and L235A of the human IgG1 Fc region, wherein the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, thereby treating the IL1R3-mediated inflammatory condition and/or disorder in the subject.
wherein the antibody or antigen binding fragment comprises: a) a VH region comprising an amino acid sequence set forth in SEQ ID NO: 28; b) a VL region comprising an amino acid sequence set forth in SEQ ID NO: 174; and c) a human IgG1 Fc region comprising at least amino acid substitutions at L234A and L235A of the human IgG1 Fc region,
a) a VH region comprising an amino acid sequence set forth in SEQ ID NO: 28;
b) a VL region comprising an amino acid sequence set forth in SEQ ID NO: 174; and
c) a human IgG1 Fc region comprising at least amino acid substitutions at L234A and L235A of the human IgG1 Fc region,
wherein the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system,
The method of claim 6 , wherein the IL1R3-mediated inflammatory condition and/or disorder is Hidradenitis Suppurativa.
A method for treating an IL1R3-mediated inflammatory condition and/or disorder in a subject, comprising administering to the subject an antibody, or antigen binding fragment thereof, that specifically binds IL-1R3, wherein the antibody or antigen binding fragment comprises: a) a VH region comprising an amino acid sequence set forth in SEQ ID NO: 28; b) a VL region comprising an amino acid sequence set forth in SEQ ID NO: 174; and c) a human IgG4 Fc region comprising at least amino acid substitutions at S228P and L235E of the human IgG4 Fc region, wherein the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, thereby treating the IL1R3-mediated inflammatory condition and/or disorder in the subject.
wherein the antibody or antigen binding fragment comprises: a) a VH region comprising an amino acid sequence set forth in SEQ ID NO: 28; b) a VL region comprising an amino acid sequence set forth in SEQ ID NO: 174; and c) a human IgG4 Fc region comprising at least amino acid substitutions at S228P and L235E of the human IgG4 Fc region,
c) a human IgG4 Fc region comprising at least amino acid substitutions at S228P and L235E of the human IgG4 Fc region,
The method of claim 8 , wherein the IL1R3-mediated inflammatory condition and/or disorder is Hidradenitis Suppurativa.
Ref US10100119: Claims:
The invention claimed is: 1. An isolated antibody with binding specificity for human interleukin-1 receptor accessory protein (IL1RAP) comprising the following complementary determining regions (CDRs): a. Heavy chain CDR1 comprising: G F T F S I Y (SEQ ID NO: 21); b. Heavy chain CDR2 comprising: S I G G S Y (SEQ ID NO: 22); c. Heavy chain CDR3 comprising: E V D G S Y A M D Y (SEQ ID NO: 23); d. Light chain CDR 1 comprising: R A S Q S I G T S I H (SEQ ID NO: 26); e. Light chain CDR2 comprising: S A S E S I S (SEQ ID NO: 27); and f. Light chain CDR3 comprising: Q Q S N S W P T T (SEQ ID NO: 28). 2. The antibody of claim 1, wherein heavy chain CDR1 comprises: G F T F S I Y T M S (SEQ ID NO: 24) and wherein heavy chain CDR2 comprises: T I S I G G S Y I N Y P D S V K G (SEQ ID NO: 25). 3. An isolated antibody with binding specificity for human interleukin-1 receptor accessory protein (IL1RAP) comprising the following complementary determining regions (CDRs): a. Heavy chain CDR1 comprising: G F T F S I Y T M S (SEQ ID NO: 24); b. Heavy chain CDR2 comprising: T I S I G G S Y I N Y P D S V K G (SEQ ID NO: 25); c. Heavy chain CDR3 comprising: E V D G S Y A M D Y (SEQ ID NO: 23); d. Light chain CDR 1 comprising: R A S Q S I G T S I H (SEQ ID NO: 26); e. Light chain CDR2 comprising: S A S E S I S (SEQ ID NO: 27); and f. Light chain CDR3 comprising: Q Q S N S W P T T (SEQ ID NO: 28). 4. The antibody of claim 1 wherein the antibody exhibits one or more of the following properties: a) a binding affinity (KD) for human IL1RAP of 500 pM or greater; b) cross-reactivity with IL1RAP from Macaca fascicularis; c) an inhibitory action on IL1 signalling; d) capability of inducing ADCC in one or more cancer cell lines; and e) capability of internalisation upon binding to one or more cancer cell lines. 5. The antibody of claim 1, wherein the antibody is an Fv fragment or an Fab fragment. 6. The antibody of claim 1 comprising a heavy chain variable region comprising or consisting of the amino acids of SEQ ID NO: 19. 7. The antibody of claim 1 comprising a light chain variable region comprising or consisting of the amino acids of SEQ ID NO: 20. 8. The antibody of claim 1 comprising a heavy chain variable region comprising or consisting of amino acids of SEQ ID NO: 19, and a light chain variable region comprising or consisting of the amino acids of SEQ ID NO: 20. 9. The antibody of claim 1 comprising an Fc region. 10. The antibody of claim 1 further comprising a cytotoxic moiety. 11. The antibody of claim 1 further comprising a detectable moiety. 12. An isolated nucleic acid molecule encoding the antibody of claim 1. 13. A pharmaceutical composition comprising the antibody of claim 8 and a pharmaceutically-acceptable diluent, carrier or excipient. 14. A method for the treatment of a neoplastic disorder in a subject, comprising administering to the subject an effective amount of the antibody of claim 1, wherein the neoplastic disorder is associated with cells expressing IL1RAP. 15. The method of claim 14, wherein the neoplastic disorder is a neoplastic hematologic disorder. 16. The method of claim 15, wherein the neoplastic hematologic disorder is selected from chronic myeloid leukemia (CML), myeloproliferative disorders (MPD), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). 17. The method of claim 14, wherein the neoplastic disorder is associated with the formation of solid tumors within the subject's body. 18. The method of claim 17, wherein the solid tumor is selected from prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer, and sarcomas.
An isolated antibody with binding specificity for human interleukin-1 receptor accessory protein (IL1RAP) comprising the following complementary determining regions (CDRs): a. Heavy chain CDR1 comprising: G F T F S I Y (SEQ ID NO: 21); b. Heavy chain CDR2 comprising: S I G G S Y (SEQ ID NO: 22); c. Heavy chain CDR3 comprising: E V D G S Y A M D Y (SEQ ID NO: 23); d. Light chain CDR 1 comprising: R A S Q S I G T S I H (SEQ ID NO: 26); e. Light chain CDR2 comprising: S A S E S I S (SEQ ID NO: 27); and f. Light chain CDR3 comprising: Q Q S N S W P T T (SEQ ID NO: 28).
The antibody of claim 1, wherein heavy chain CDR1 comprises: G F T F S I Y T M S (SEQ ID NO: 24) and wherein heavy chain CDR2 comprises: T I S I G G S Y I N Y P D S V K G (SEQ ID NO: 25).
An isolated antibody with binding specificity for human interleukin-1 receptor accessory protein (IL1RAP) comprising the following complementary determining regions (CDRs): a. Heavy chain CDR1 comprising: G F T F S I Y T M S (SEQ ID NO: 24); b. Heavy chain CDR2 comprising: T I S I G G S Y I N Y P D S V K G (SEQ ID NO: 25); c. Heavy chain CDR3 comprising: E V D G S Y A M D Y (SEQ ID NO: 23); d. Light chain CDR 1 comprising: R A S Q S I G T S I H (SEQ ID NO: 26); e. Light chain CDR2 comprising: S A S E S I S (SEQ ID NO: 27); and f. Light chain CDR3 comprising: Q Q S N S W P T T (SEQ ID NO: 28).
The antibody of claim 1 wherein the antibody exhibits one or more of the following properties: a) a binding affinity (KD) for human IL1RAP of 500 pM or greater; b) cross-reactivity with IL1RAP from Macaca fascicularis; c) an inhibitory action on IL1 signalling; d) capability of inducing ADCC in one or more cancer cell lines; and e) capability of internalisation upon binding to one or more cancer cell lines.
The antibody of claim 1, wherein the antibody is an Fv fragment or an Fab fragment.
The antibody of claim 1 comprising a heavy chain variable region comprising or consisting of the amino acids of SEQ ID NO: 19.
The antibody of claim 1 comprising a light chain variable region comprising or consisting of the amino acids of SEQ ID NO: 20.
The antibody of claim 1 comprising a heavy chain variable region comprising or consisting of amino acids of SEQ ID NO: 19, and a light chain variable region comprising or consisting of the amino acids of SEQ ID NO: 20.
The antibody of claim 1 comprising an Fc region.
The antibody of claim 1 further comprising a cytotoxic moiety.
The antibody of claim 1 further comprising a detectable moiety.
An isolated nucleic acid molecule encoding the antibody of claim 1.
A pharmaceutical composition comprising the antibody of claim 8 and a pharmaceutically-acceptable diluent, carrier or excipient.
A method for the treatment of a neoplastic disorder in a subject, comprising administering to the subject an effective amount of the antibody of claim 1, wherein the neoplastic disorder is associated with cells expressing IL1RAP.
The method of claim 14, wherein the neoplastic disorder is a neoplastic hematologic disorder.
The method of claim 15, wherein the neoplastic hematologic disorder is selected from chronic myeloid leukemia (CML), myeloproliferative disorders (MPD), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
The method of claim 14, wherein the neoplastic disorder is associated with the formation of solid tumors within the subject's body.
The method of claim 17, wherein the solid tumor is selected from prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer, and sarcomas.
Ref US9403906: Claims:
The invention claimed is: 1. A method for treating a solid tumor selected from colon cancer, lung cancer, breast cancer and melanoma in a human, comprising administering to the human an effective amount of an anti-interleukin-1 receptor accessory protein (IL1RAP) antibody with specificity for an extracellular domain of human IL1RAP wherein cells of the solid tumor express IL1RAP. 2. The method according to claim 1, wherein the solid tumor is selected from the group consisting of breast ductal carcinoma, lung cancer, and colon cancer. 3. The method according to claim 1, wherein the solid tumor is a melanoma. 4. The method according to claim 1, wherein the antibody is a monoclonal antibody. 5. The method according to claim 4, wherein the monoclonal antibody is human or humanized. 6. The method according to claim 1, wherein the antibody further comprises a cytotoxic or detectable moiety. 7. The method according to claim 6, wherein the cytotoxic or detectable moiety comprises or consists of a radioisotope. 8. The method according to claim 7, wherein the radioisotope is selected from the group consisting of astatine-211, bismuth-212, bismuth-213, iodine-131, yttrium-90, lutetium-177, samarium-153 and palladium-109. 9. The method according to claim 6, wherein the cytotoxic moiety comprises or consists of a toxin. 10. The method according to claim 6, wherein the cytotoxic moiety comprises or consists of a chemotherapeutic agent. 11. The method according to claim 7, wherein the radioisotope is selected from the group consisting of technitium-99m, indium-111, gallium-67, gallium-68, arsenic-72, zirconium-89, iodine-12 and thallium-201. 12. The method of claim 1, wherein the antibody induces antibody-dependent cell-mediated cytotoxicity (ADCC). 13. The method of claim 1, wherein the antibody is of IgG1 isotype. 14. The method of claim 1, wherein the antibody is of IgG2a isotype. 15. The method of claim 1, wherein the antibody is administered parenterally. 16. The method of claim 15, wherein the parenteral administration is intravenous, subcutaneous, or intramuscular. 17. A method for reducing the size and/or reducing the growth of a solid tumor selected from colon cancer, lung cancer, breast cancer and melanoma in a human, comprising administering to an individual an effective amount of an anti-interleukin-1 receptor accessory protein (IL1RAP) antibody with specificity for an extracellular domain of human IL1RAP wherein cells of the solid tumor express IL1RAP. 18. The method according to claim 17, wherein the solid tumor is selected from the group consisting of breast ductal carcinoma cancer, lung cancer, colon cancer, and melanoma. 19. The method according to claim 17, wherein the antibody is a monoclonal antibody. 20. The method of claim 17, wherein the antibody is of IgG1 isotype. 21. The method of claim 17, wherein the antibody is of IgG2a isotype.
A method for treating a solid tumor selected from colon cancer, lung cancer, breast cancer and melanoma in a human, comprising administering to the human an effective amount of an anti-interleukin-1 receptor accessory protein (IL1RAP) antibody with specificity for an extracellular domain of human IL1RAP wherein cells of the solid tumor express IL1RAP.
The method according to claim 1, wherein the solid tumor is selected from the group consisting of breast ductal carcinoma, lung cancer, and colon cancer.
The method according to claim 1, wherein the solid tumor is a melanoma.
The method according to claim 1, wherein the antibody is a monoclonal antibody.
The method according to claim 4, wherein the monoclonal antibody is human or humanized.
The method according to claim 1, wherein the antibody further comprises a cytotoxic or detectable moiety.
The method according to claim 6, wherein the cytotoxic or detectable moiety comprises or consists of a radioisotope.
The method according to claim 7, wherein the radioisotope is selected from the group consisting of astatine-211, bismuth-212, bismuth-213, iodine-131, yttrium-90, lutetium-177, samarium-153 and palladium-109.
The method according to claim 6, wherein the cytotoxic moiety comprises or consists of a toxin.
The method according to claim 6, wherein the cytotoxic moiety comprises or consists of a chemotherapeutic agent.
The method according to claim 7, wherein the radioisotope is selected from the group consisting of technitium-99m, indium-111, gallium-67, gallium-68, arsenic-72, zirconium-89, iodine-12 and thallium-201.
The method of claim 1, wherein the antibody induces antibody-dependent cell-mediated cytotoxicity (ADCC).
The method of claim 1, wherein the antibody is of IgG1 isotype.
The method of claim 1, wherein the antibody is of IgG2a isotype.
The method of claim 1, wherein the antibody is administered parenterally.
The method of claim 15, wherein the parenteral administration is intravenous, subcutaneous, or intramuscular.
A method for reducing the size and/or reducing the growth of a solid tumor selected from colon cancer, lung cancer, breast cancer and melanoma in 
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