DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The preliminary amendment filed on 04/06/2023 cancelled claims 1-10 and 21-40. There are no claims withdrawn and no claims amended. Claims 11-20 are pending and will be examined on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statements filed on 04/06/2023, 07/16/2024, 1/22/2025, and 11/24/2025 have been considered. Signed copies are enclosed.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 19 is objected to because of the following informalities: Claim 19 states "The therapeutic method according to claim 11 which is combined with a known topical agent such as a steroid." The combination of a method and an object (i.e. a topical agent) is improper and unclear. Claim 19 should read “The therapeutic method according to claim 11 which is combined with the use of a known topical agent such as a steroid” or similar. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 20 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 term “KHK4083” in claim 20 is a relative term which renders the claim indefinite. The term “KHK4083” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. KHK4083 is a characterization of the antibody and has no meaning to a person skilled in the art. Therefore, the anti-OX40 antibody of claim 20 is indefinite.
Claim Rejections - 35 USC § 112(a)
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 11are 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 claim(s) contains 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 inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim 11 recites “a therapeutic method for an OX40-related immune- or allergy-related disease including subcutaneously administering an anti-OX40 antibody to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose.” Claims 14, 17, and 18 limit the OX40-related immune or allergy-related disease to atopic dermatitis. Claims 13, 15, 16, and 19 further limit the administration of the anti-OX40 antibody of claim 11, where claim 13 limits the length of administration (“continued for at least 16 weeks, 20 weeks, 22 weeks, 24 weeks or 34 weeks after starting”), 15 limits the frequency of administration (“administered once in two weeks, three weeks or four weeks”), 16 limits the dose of anti-OX40 antibody (“the dose is selected from 150 mg, 300 mg, 450 mg and 600 mg”), and 19 combines this administration method with “a known topical agent such as a steroid.” Therefore, claims 11, 13, 15, 16, and 19 encompass any anti-OX40 antibody and any OX40-related immune or allergy-related disease, while claims 14, 17, and 18 encompass any anti-OX40 antibody.
Claims 12 and 20 further limit the anti-OX40 antibody, stating “the anti-OX40 antibody is a monoclonal antibody containing a heavy chain variable region (also called VH) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (also called VL) containing the amino acid sequence of SEQ ID NO: 2” and “the anti-0X40 antibody is KHK4083”. Therefore, claim 12 encompasses any anti-OX40 antibody that has the VH and VL of SEQ IDs NO:1 and NO:2, respectively, and claim 20 encompasses the indefinite anti-OX40 antibody KHK4083 (see above), and claims 12 and 20 encompass any OX40-related immune or allergy-related disease.
The specification states that an OX40-related immune or allergy-related disease may be “asthma, inflammatory bowel disease, transplant rejection, autoimmune diabetes, graft versus host disease (GvHD), arthritis, or experimental autoimmune encephalomyelitis” (paragraph [0044]), and later, in paragraph [0071], states “In other embodiments, the OX40-mediate disease comprises infections (viral, bacterial, fungal and parasitic, endotoxic shock associated with infection, arthritis, rheumatoid arthritis, asthma, bronchitis, influenza, respiratory syncytial virus, pneumonia, COPD, idiopathic pulmonary fibrosis (IPF), cryptogenic fibrosing alveolitis (CF A), idiopathic fibrosing interstitial pneumonia, emphysema, pelvic inflammatory disease, Alzheimer's Disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Peyronie's Disease, coehac disease, gallbladder disease, Pilonidal disease, peritonitis, psoriasis, vasculitis, surgical adhesions, stroke, Type I Diabetes, lyme disease, arthritis, meningoencephalitis, autoimmune uveitis, immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis, lupus (such as systemic lupus erythematosus) and Guillain-Barr syndrome, Atopic dermatitis, wherein atopic dermatitis is mild, or mild-to-moderate, or moderate, or moderate-to-severe, or severe, autoimmune hepatitis, fibrosing alveolitis, Grave's disease, IgA nephropathy, idiopathic thrombocytopenic purpura, Meniere's disease, pemphigus, primary biliary cirrhosis, sarcoidosis, scleroderma, Wegener's granulomatosis, other autoimmune disorders, pancreatitis, trauma (surgery), graftversus-host disease (GVHD), transplant rejection, cardiovascular disease including ischaemic diseases such as myocardial infarction as well as atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, osteoarthritis, periodontitis, hypochlorhydia, hidradenitis and neuromyelitis optica” (verbatim). The specification teaches the use of the claimed method to treat “patients with moderate to severe atopic dermatitis (AD) which is poorly controllable using a topical agent and moderate to severe AD patients to whom topical therapies are not medically recommended.” The specification teaches that treating AD patients with the claimed therapeutic method of claim 11 yields “excellent improvement effects”, and that continuous administration after the first 16 week treatment period further enhanced the improvement effects, as well as their lasting effects (see paragraph [0203]).
In regards to the anti-OX40 antibody, the specification teaches that, by an anti-OX40 antibody, the applicant refers to “antibodies or a fragment thereof that binds to…OX40 in isolated form” [0033]. The specification also teaches that an “"antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding fragment thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL” [0035]. These are consistent with generally accepted definitions of an antibody in the art. The specification does state “Examples of the constant regions contained in the anti-OX40 antibody of the invention include a constant region containing the amino acid sequence of SEQ ID NO: 3 and a constant region containing the amino acid sequence of SEQ ID NO: 4. An example of the anti-OX40 antibody of the invention is a monoclonal antibody containing a heavy chain containing the amino acid sequence of SEQ ID NO: 5 and a light chain containing the amino acid sequence of SEQ ID NO: 6” [0039]. Additionally, the antibody used in the specification is monoclonal antibody “KHK4083” [0040], [0099]. All data described in the specification was generated with the use of this “KHK4083” clone.
Claims 11-13, 15, 16, 19, and 20 are broadly drawn to a therapeutic method for an OX40-related immune- or allergy-related disease, which is interpreted as set forth in paragraph [0044] of the specification as “asthma, inflammatory bowel disease, transplant rejection, autoimmune diabetes, graft versus host disease (GvHD), arthritis, or experimental autoimmune encephalomyelitis” and the extensive list set forth in paragraph [0071] of the specification (see above).
The specification has written description support for the specific therapeutic method including subcutaneously administering the anti-OX40 antibody the specification calls “KHK4083” to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose for 36 weeks in moderate to severe AD patients. However, the specification does not teach the use of the therapeutic method of claim 11 in asthma, inflammatory bowel disease, transplant rejection, autoimmune diabetes, GvHD, arthritis, or experimental autoimmune encephalomyelitis, nor any other listed disease apart from atopic dermatitis, and therefore does not encompass the recited breadth of the claims.
The specification is therefore not deemed sufficient to reasonably convey to one skilled in the art that the inventors, at the time the invention was made, had possession of treating the list of OX40-related immune- or allergy-related diseases.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The claims speak to a broad genus of “OX40-related immune- or allergy-related diseases”, and the specification provides evidence for one species within this genus, moderate to severe atopic dermatitis. According to the MPEP §2163:
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[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.' (internal quotation marks omitted).").
A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).”
The state of the art regarding therapeutic methods for immune and allergy related diseases, conditions commonly referred to as autoimmune disorders, can be briefly reviewed in Miescher et al. (Springer Semin Immun 25 (Suppl 1), S5–S60 (2003)). Miescher et al. teach many possible causes and manifestations of autoimmune conditions and address the variability of disease manifestations from patient to patient, or even within the same patient over the course of the disease. This extreme variability makes uniform treatment of these conditions difficult (see page S54-S55). A review assembled by Webb et al. (Clinic Rev Allerg Immunol 50, 312–332 (2016)) discusses the interactions between the OX40-OX40L axis and autoimmune disease, and discusses both the advantages of targeting this axis, as well as potential problems (Box 1 and Box 2). Importantly, Webb et al. teach unexpected disease exacerbation in some models where OX40 signaling is targeted, as well as vulnerability to infection or other disease complications. Webb et al. also emphasize that a majority of studies on OX40-related treatment have been performed in animal models, which do not always translate to clinical human applications, and even cite some instances where there are obvious differences in therapeutic mechanisms between animal models and humans; i.e., human Tregs do not express OX40 (see box 2). Furthermore, Kierkus et al. (Crohn’s & Colitis, July 2020; 2 (3):1-10) demonstrated the attempted use of the claimed “KHK4083” antibody as a treatment in a clinical trial for ulcerative colitis (UC). The treatment works scientifically, in reducing OX40+ cells, but provides no clinical remediation in UC patients, indicating that one of the diseases listed by the applicant in the specification (UC; see paragraph [0071]) does not respond to treatment with this antibody and provides no symptomatic alleviation.
Taken together, the state of the art suggests that OX40-mediated immune and allergy related diseases, or autoimmune diseases, react differently to treatment, and the exact role of OX40 in these conditions is still being elucidated. Accordingly, one of skill in the art would conclude that the claimed invention encompasses a broad genus of autoimmune disorders that may not all respond to treatment with an OX40 antagonist. While the specification has demonstrated treating a single OX40-mediated autoimmune disease, one of skill in the art would not deem the prior art in autoimmune disease treatment to be predicative of the efficacy of the claimed treatment on all the listed OX40 diseases. Based on the teaching of the instant specification and the prior art, one of skill in the art would not conclude that Applicant was in possession of the claimed genus of OX40-mediated immune or allergy related diseases.
Consequently, the therapeutic method for treating the list of OX40-mediated immune or allergy related diseases defined in the specification, including subcutaneously administering an anti-OX40 antibody to a patient, does not meet the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The applicant has not disclosed any species representative of the genus, which is variant.
Claims 11-20 are drawn to “an anti-OX40 antibody” or the antibody of claim 12 (as claim 20 is indefinite). The specification provides written description support for the use of the antibody referred to as “KHK4083” in the claimed method. However, the claims are primarily directed to encompass any anti-OX40 antibody, and are, in claim 12, directed to any anti-OX40 antibody with the heavy and light variable sequences defined. None of these antibodies meets the written description provision of 35 USC 112(a), as the specification is silent as to what “immunoepitopes” and/or CDRs are required for a given antibody to bind to OX40 and therefore does not encompass the recited breadth of the claims. Moreover, the specification is silent with regard to what constant regions must be present for a given antibody to have the recited immunological properties and therefore does not encompass the recited breadth of the claims.
Claims 11 and 13-19 speak to “an anti-OX40 antibody” that can be used therapeutically for an OX40-related immune- or allergy-related disease. As such, the claim is directed to an antibody defined entirely by function (binding). In claim 12, the claims are directed to any anti-OX40 antibody with the heavy and light variable sequences defined, with no limitations regarding the constant, or framework, regions. Additionally, the claims speak to the broad genus of “anti-OX40 antibodies”, and the specification provides evidence for one species within this genus – the “KHK4083” clone.
To fulfill the written description requirements set forth under 35 U.S.C. 112(a), the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession of the claimed invention. To adequately describe the genus of antibodies, Applicant must adequately describe which combination of variable regions and framework regions that give rise to an antibody with the claimed immunological function. The instant specification, however, does not disclose distinguishing and identifying features of a representative number of members of the genus of antibodies to which the claims are drawn, such as a correlation between the structure of the antibody and its recited function (OX40 antagonism), so that the skilled artisan could immediately envision, or recognize, at least a substantial number of members of the claimed genus of antibodies. The specification fails to disclose what combination of variable regions and framework regions (other than those of the KHK4083 antibody) are essential for antibody binding, or which amino acids might be added, replaced or deleted so that the resultant antibody retains the binding specificity of its parent, or by which other amino acids the essential amino acids might be replaced so that the resultant antibody retains the binding specificity of its parent. Therefore, the specification fails to adequately describe at least a substantial number of members of the genus of antibodies to which the claims refer; and accordingly, the specification fails to adequately describe at least a substantial number of members of the claimed genus of antibodies.
MPEP §2163 states:
“An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. For example, the amino acid sequence of a protein along with knowledge of the genetic code might put an inventor in possession of the genus of nucleic acids capable of encoding the protein, but the same information would not place the inventor in possession of the naturally-occurring DNA or mRNA encoding the protein. See In re Bell, 991 F.2d 781, 26 USPQ2d 1529 (Fed. Cir. 1993); In re Deuel, 51 F.3d 1552, 34 USPQ2d 1210 (Fed. Cir. 1995).”
The MPEP §2163 is also quoted above (see page 11) and additionally states:
“For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).”
As evidenced by the teachings of Skolnick et al., the art is unpredictable. Skolnick et al. (Trends in Biotechnology 18: 34-39, 2000) discloses the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (see, e.g., the abstract; and page 34, Sequence-based approaches to function prediction). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to the function of the structurally related protein (see, in particular, the abstract and Box 2). Thus, one skilled in the art would not accept the assertion, which is based only upon an observed similarity in amino acid sequence that a variant of a given polypeptide would necessarily bind to a given antibody. Moreover, as evidenced by Greenspan et al. (Nature Biotechnology 7: 936-937, 1999), defining epitopes is not as easy as it seems. Greenspan et al. recommends defining an epitope by the structural characterization of the molecular interface between the antigen and the antibody is necessary to define an "epitope" (page 937, column 2). According to Greenspan et al., an epitope will include residues that make contacts with a ligand, here the antibody, but are energetically neutral, or even destabilizing to binding. Furthermore, an epitope will not include any residue not contacted by the antibody, even though substitution of such a residue might profoundly affect binding. Accordingly, it follows that the immunoepitopes that can elicit antibodies that bind to a given antigen can only be identified empirically. Therefore, absent a detailed and particular description of a representative number, or at least a substantial number of the members of the genus of immunoepitopes, the skilled artisan could not immediately recognize or distinguish members of the claimed genus of antibodies.
It is well settled that the exchanging of CDRs among between antibodies is not predictable. While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen- binding domains and surrounding framework regions of antibodies. For example, Giusti et al. (Proc. Natl. Acad. Sci. USA. 1987 May; 84 (9): 2926-2930) teaches the specificity and affinity of an antibody is exquisitely sensitive to amino acid substitutions within the primary structure of the antibody, since only a single amino acid substitution in the heavy chain of an antibody completely altered the binding specificity of an antibody that binds phosphocholine, such that the altered antibody fails to bind phosphocholine but instead binds DNA (see entire document [e.g., the abstract]). This unpredictability of single amino acid changes in an antibody is underscored by Winkler et al (J Immunol. 2000 Oct 15; 165 (8): 4505-14.) who teach that single amino acid changes in antibody side chains can result in unpredictable and substantial changes in antibody specificity; (see entire document [e.g., the abstract]). Chien et al. (Proc. Natl. Acad. Sci. USA. 1989 Jul; 86 (14): 5532-5536) teaches that significant structural and functional changes in an antigen-binding site can be caused by amino acid substitutions in the primary structure of an antibody, including substitutions at a site remote from the complementarity determining regions of the antigen- binding domain; (see entire document [e.g., the abstract]). Similarly, but more recently, Caldas et al. (Mol. Immunol. 2003 May; 39 (15): 941-952) teaches an unexpected effect of substituting a framework residue upon binding specificity during the humanization of an antibody that binds CD18 (see entire document [e.g., the abstract]). Casadevall et al. (PNAS 2012; Vol 109 No. 31, pages 12272-12273) underscores the importance of the framework regions with regard to antibody affinity and binding specificity.
Sela-Culang et al. (Frontiers in Immunology, 2013 Vol. 4, article 302, pages 1-13) clearly set forth the role of CDRs, framework regions, and constant regions in antibody specificity and affinity. Sela-Culang et al. disclose that the belief CDRs of an antibody are responsible for antigen recognition while the constant domains mediate effector activation is an oversimplification, and that some residues within the CDRs never participate in antigen binding while some off-CDR residues are critical for antigen interaction. Sela-Culang et al. further disclose that only 20-33% of the residues within the CDRs actually participate in antigen binding (see page 4) and that it is well established that some of the framework (FR) residues play an important role in antigen binding (see page 7). This point is demonstrated by the fact that humanizing an antibody by grafting only the CDRs usually results in a significant drop or complete loss of antigen binding. Sela-Culang et al. also discloses that the framework region residues that affect binding can be divided into two categories: those that contact the antigen (which can be close in sequence to the CDRs or far from the CDRs in sequence but are in close proximity to it in 3-D structure) and those that are not in contact with the antigen but affect antigen binding indirectly (which can be in spatial proximity to the CDRs or not). The framework regions residues that are more distant from the paratope (i.e. binding residues) not only play a role in maintaining the overall structure of the variable (Fv) domains but may affect antigen binding itself by directing the relative orientation of the VH with relation to the VL and thus the orientation of the CDRs relative to each other (see page 7). Specific knowledge of the FR residues involved in antigen binding is critical for antibody design in general and for the humanization of antibodies in particular. Finally, Sela-Culang et al. disclose that the constant regions of antibodies play a role in antigen binding due to an allosteric influence of the constant domains on the structure of the variable domains as evidenced by the differences in affinity and specificities of antibodies with the same variable region but different isotypes (see page 8).
Recently, describing antibodies by their functions was addressed in the Centocor decision (CENTOCOR ORTHO BIOTECH, INC. v ABBOTT LABORATORIES (Fed Cir, 2010-1144, 2/23/2011)). In said case the court stated:
“To satisfy the written description requirement, "the applicant must ‘convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention,’ and demonstrate that by disclosure in the specification of the patent." Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008) (quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991)). Assessing such "possession as shown in the disclosure" requires "an objective inquiry into the four corners of the specification.” Ariad, 598 F.3d at 1351. Ultimately, "the specification must describe an invention understandable to [a person of ordinary skill in the art] and show that the inventor actually invented the invention claimed." Id. A "mere wish or plan" for obtaining the claimed invention is not adequate written description. Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997).”
The court further opined that Centocor's suggestion
“that our decision in Noelle and the PTO written description guidelines support the view that fully disclosing the human TNF-α protein provides adequate written description for any antibody that binds to human TNF-α. That suggestion is based on an unduly broad characterization of the guidelines and our precedent.”
The court concluded that
“While our precedent suggests that written description for certain antibody claims can be satisfied by disclosing a well-characterized antigen, that reasoning applies to disclosure of newly characterized antigens where creation of the claimed antibodies is routine. Claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described.
Moreover, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) recently decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 P.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (ed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Even more recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided (and was subsequently unanimously upheld by the U.S. Supreme Court) Amgen v. Sanofi, Aventisub LLC, 987 F.3d 1080, 2021 US.P.Q.2d 169 (Fed. Cir. 2021), which concerned enablement for claims drawn to antibodies. While said case was dealt with enablement it should be noted that:
“One of Amgen's expert witnesses admitted that translating an antibody's amino acid "sequence into a known three-dimensional structure is still not possible." J.A. 3910; see also Decision, 2019 U.S. Dist. LEXIS 146305, at *9 . Another of Amgen's experts conceded that "substitutions in the amino acid sequence of an antibody can affect the antibody's function, and testing would be required to ensure that a substitution does not alter the binding and blocking functions." J.A. 3891; see also Decision, 2019 U.S. Dist. LEXIS 146305, at *9 .
Said expert testimony illustrates the unpredictability of the antibody arts and clearly sets forth the expectations of the skilled artisan.
Consequently, because the art is unpredictable, in accordance with the MPEP, only the “KHK4083” antibody clone, but not the full breadth of the claims, meets the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Applicant is reminded that Vas- Cath makes clear that the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision. (See page 1115).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 11 and 14-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Back et al., WO 2019/229155 A1, 2019 (hereinafter known as Back).
Claim 11 describes a therapeutic method for an OX40-related immune- or allergy-related disease including subcutaneously administering an anti-OX40 antibody to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose, with claims 14-18 further specifying variations in the 2-4 week window and the 150-600 mg dose, as well as the application of the therapeutic method to cases of moderate to severe atopic dermatitis which is poorly controllable using a topical agent.
Back teaches a therapeutic method for an OX-40 mediated disease (abstract, introduction) that includes subcutaneous administration of an anti-OX40 antibody to a patient at a dose of 300 mg once every two weeks continuously at the same dose in Example 3 (see table 85), teaching claims 11, 15, and 16. The therapeutic method of Back is administered to patients with moderate to severe atopic dermatitis which is poorly controllable using topical agents (Example 3, page 109, line 11), thereby meeting claims 14, 17, and 18. Therefore, the therapeutic method of Beck anticipates the claimed invention of claims 11 and 14-18.
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.
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 11-12, 14-18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Back et al., WO 2019/229155 A1, 2019 (hereinafter known as Back) in view of Papp et al., JEADV (2017); 31:1324-1332 (hereinafter Papp).
Claim 11 describes a therapeutic method for an OX40-related immune- or allergy-related disease including subcutaneously administering an anti-OX40 antibody to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose, with claims 14-18 further specifying variations in the 2-4 week window and the 150-600 mg dose, as well as the application of the therapeutic method to cases of moderate to severe atopic dermatitis which is poorly controllable using a topical agent.
Claim 12 is drawn to the use an antibody with specified variable regions in the method of claim 11, and claim 20 is drawn to the use of the antibody KHK4083 in the method of claim 11.
Back teaches a therapeutic method for an OX-40 mediated disease (abstract, introduction) that includes subcutaneous administration of an anti-OX40 antibody to a patient at a dose of 300 mg once every two weeks continuously at the same dose in Example 3 (see table 85), teaching claims 11, 15, and 16. The therapeutic method of Back is administered to patients with moderate to severe atopic dermatitis which is poorly controllable using topical agents (Example 3, page 109, line 11), thereby meeting claims 14, 17, and 18. Therefore, the therapeutic method of Beck anticipates the claimed invention of claims 11 and 14-18. Additionally, Back teaches that the absolute bioavailability of the tested anti-OX40 antibody GBR830 (page 104 line 3).
Back does not teach the use of the specific antibody of instant claims 12 and 20.
Papp teaches the use of the anti-OX40 antibody of claims 12 and 20, KHK4083, in treatment of plaque psoriasis, an autoimmune skin disease mediated similarly to atopic dermatitis. Papp compares IV administration of KHK4083 with subcutaneous (SC) administration. Papp showed a greater response when the antibody was SC administered (page 1332 left column), providing a strong indication that SC administration of KHK4083 is more advantageous than IV administration. As a first-in-human study of this antibody, Papp calls for further testing using repeated doses via SC administration of KHK4083. Papp also teaches the bioavailability for KHK4083 after SC administration is higher than that taught by Back (page 1332 left column).
Taking this information together, a person of ordinary skill in the art of atopic dermatitis treatment, before the effective filing date of the invention, would have been motivated to combine the method of Back with the antibody of Papp. The antibody of Papp has a higher absolute bioavailability than then antibody of Back, which is defined as “the proportion of a drug or other substance which enters the circulation when introduced into the body and so is able to have an active effect.” With the knowledge there is more antibody available when the antibody of Papp is administered, one skilled in the art would be motivated to substitute the antibody of Papp in place of the antibody of Back, as the antibodies target the same receptor.
Additionally, the administration method of Back provides higher, repeated doses for the SC administration of anti-OX40 antibodies, as called for by Papp. Applying the method of Back to the antibody of Papp would have been obvious to one skilled in the art of antibody treatment, as the antibodies target the same molecule and extended administration is indicated in Papp.
Finally, atopic dermatitis and plaque psoriasis are closely related autoimmune skin diseases, and indeed, Back names plaque psoriasis as an “OX40-mediated disease” on page 29, line 15.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to use the antibody of Papp with the administration method of Back to treat atopic dermatitis.
Claims 11 and 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Back in view of Blauvelt et al., Lancet (2017); 389:2287-303 (hereinafter Blauvelt).
Claim 11 describes a therapeutic method for an OX40-related immune- or allergy-related disease including subcutaneously administering an anti-OX40 antibody to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose, with claims 14-18 further specifying variations in the 2-4 week window and the 150-600 mg dose, as well as the application of the therapeutic method to cases of moderate to severe atopic dermatitis which is poorly controllable using a topical agent.
Claim 13 is drawn to extending the method of claim 11 for at least 16 weeks, 20 weeks, 22 weeks, 24 weeks or 34 weeks after starting the administration.
Back teaches a therapeutic method for an OX-40 mediated disease (abstract, introduction) that includes subcutaneous administration of an anti-OX40 antibody to a patient at a dose of 300 mg once every two weeks continuously at the same dose in Example 3 (see table 85), teaching claims 11, 15, and 16. The therapeutic method of Back is administered to patients with moderate to severe atopic dermatitis which is poorly controllable using topical agents (Example 3, page 109, line 11), thereby meeting claims 14, 17, and 18. Therefore, the therapeutic method of Beck anticipates the claimed invention of claims 11 and 14-18.
Back does not teach the administration of this therapeutic method for at least 16 weeks, 20 weeks, 22 weeks, 24 weeks, or 34 weeks after starting the administration, as stated in instant claim 13.
Blauvelt teaches the treatment of atopic dermatitis with a different antibody (dupilumab) every 2 weeks at a dose of 300 mg, with administration continuing for 52 weeks. Blauvelt explains that the 52-week duration of the study allowed the antibody to treat atopic dermatitis (AD) flares over time, a common AD disease manifestation. Blauvelt shows that the administration of the antibody reduced flare rates and fewer patients experienced adverse events of AD exacerbation (Page 2300, left column, paragraph 3).
Therefore, one of ordinary skill in the art of atopic dermatitis treatment, based on the teachings of Blauvelt, would be motivated to extend the treatment of Back for at least 16, 20, 22, 24, or 36 weeks, as in instant claim 13, because Blauvelt has demonstrated that longer administration of antibody treatment results in more positive patient outcomes, such as reduced flare rates and fewer adverse events. Thus, it would have been prima facie obvious to one of ordinary skill of the art before the effective filing date of the invention to combine the administration method of Back and the length of administration of Blauvelt to improve patient outcomes.
Claims 11 and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Back in view of Lin et al., WO 2018/057849 A1, 2018 (hereinafter known as Lin).
Claim 11 describes a therapeutic method for an OX40-related immune- or allergy-related disease including subcutaneously administering an anti-OX40 antibody to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose, with claims 14-18 further specifying variations in the 2-4 week window and the 150-600 mg dose, as well as the application of the therapeutic method to cases of moderate to severe atopic dermatitis which is poorly controllable using a topical agent.
Claim 19 further limits claim 11 with the combination of this therapeutic method with a topical agent such as a steroid.
Back teaches a therapeutic method for an OX-40 mediated disease (abstract, introduction) that includes subcutaneous administration of an anti-OX40 antibody to a patient at a dose of 300 mg once every two weeks continuously at the same dose in Example 3 (see table 85), teaching claims 11, 15, and 16. The therapeutic method of Back is administered to patients with moderate to severe atopic dermatitis which is poorly controllable using topical agents (Example 3, page 109, line 11), thereby meeting claims 14, 17, and 18. Therefore, the therapeutic method of Beck anticipates the claimed invention of claims 11 and 14-18.
Back does not teach the combination of this therapeutic method and a known topical agent as in instant claim 19.
Lin does teach a therapeutic method for moderate to severe atopic dermatitis comprising subcutaneous administration of an antibody at a dose of 150 mg to 600 mg once in two to four weeks continuously at the same dose, as well as the administration of the antibody therapy combined with a known topical agent (see claims 105 and 106 of Lin). Therefore, Lin teaches claim 19 that Back does not teach.
Paragraphs [00238-00239] of Lin state that application of a topical corticosteroid (referred to as TCS) in addition to antibody therapy was incorporated into this study to improve patient compliance in the control arm, and provides support that the inclusion of TCS improved patient participation in the placebo arm of the study. Lin points out that there was a high compliance rate, of 88%, to TCS administration in all treatment groups of the study. Lin also shows improvement in study results across all arms of the study, with an increased improvement rate when antibody therapy was combined with TCS usage, which indicates that TCS administration improves patient outcomes.
Taken together, prior to the effective filing date of the instant application, one of ordinary skill in the art of atopic dermatitis treatment would have been motivated to combine the administration method of the anti-OX40 antibody of Back with the administration of a topical agent, such as the topical corticosteroid of Lin, in order to increase patient compliance and decrease patient dropout in their study, as well as to improve patient outcomes, as seen in Lin.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the invention to combine the therapeutic method of Back with the administration of a TCS as indicated by Lin to improve patient outcomes.
Conclusion
Claims 11-20 are rejected; no claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Nakagawa H et al., Journal of Dermatological Science, 2020.06.13, 82-89. Nakagawa is prior art to the instant application and includes the administration of KHK4083 to patients with moderate-to-severe atopic dermatitis.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amelia C Stephens whose telephone number is (571)272-1006. The examiner can normally be reached M-F 8-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMELIA STEPHENS/ Examiner, Art Unit 1645
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674