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 .
Claims Status
The Amendment filed on 03/15/2024 is acknowledged in which claim(s) 4, 7-8, 10-12, 16-53, 56-61, 63-64, 70-71, 73, 76-77, 80-85, 87-92, 98-99, 101, 104-105 were canceled by the Applicant.
Claims 1-3, 5-6, 9, 13-15, 54-55, 62, 65-69, 72-75, 78-79, 86, 93-97, 100, 102-103 are presented for examination on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/25/2024 and 03/12/2024 has been considered by the Examiner. An initialed copy of the form PTO-1449 is attached to the office action.
Drawings
The drawings are objected to because TEPEZZA should have a trademark (®) on Figures 1-7. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code [e.g., paragraph 0024]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 15 is objected to because of the following informality:
“Robatumumab” is repeated (twice) in line 3.
Appropriate correction is required.
Claims 65 and 93 are objected to because of the following informalities:
In lines 3-14, the use of periods within the text of the claims to denote sequence sets “a.”, “b.”, “c.”, “d.”, “e.”, and “f.” Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Freesola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Appropriate correction is required.
Claims 69 and 72 are objected to because of the following informalities:
“IGF1R” is misspelled in line 1 and is written as “IGFR.”
Appropriate correction is required.
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 65 and 93 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 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.
Claimed Invention:
Claims 65 and 93 are drawn to a method of treating inactive or chronic TED comprised of an antibody that binds to and inhibits IGF1R, wherein the antibody is defined by any one of the recited CDR sequences. The claim limitations as written require only one (a) light chain CDR (e.g., LCDR1), or (b) one heavy chain CDR (e.g., HCDR2), which is less than half an antibody binding site missing either (a) the remaining LCDRs (e.g., LCDR2-3) and the HCDR compliment (e.g., HCDR1-3), or (b) the remaining HCDRs (e.g., HCDR1 and 3) and the LCDR compliment (e.g., LCDR1-3) that would create the full antibody binding site (e.g., 6 CDRs) that functions to bind and inhibit IGF1R to treat inactive or chronic TED.
Scope of Disclosed Species
The instant specification teaches administering an IGF1R-inhibiting antibody, comprising immunoglobulin HCDR1-3 and immunoglobulin LCDR1-3, comprising the amino acid sequences set forth in SEQ ID NOs 1-6, which is identified as teprotumumab, as evidenced by a SciFinder substance search, which discloses a 100% match between the amino acid sequences set forth in SEQ ID NOs 1-6 in the instant application (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details). The instant speciation does not disclose any other anti-IGFR1 antibody comprising SEQ ID NOs: 1, 2, 3, 4, 5 OR 6 that will bind to IGF1R and inhibit its function as required by the instant specification.
State of the Prior Art
At the time of filing, antibody functionality was known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that mutation to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang et al. (Fron. Immunol., 4:302, 07 October 2013; hereinafter “Sela-Culang”) reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition (e.g., page 1, abstract; pages 3-7, “The Role of CDRs and their Definition”). A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized (e.g., pages 1-3, “The Motivations for, and Applications of, the Study of Ab-Ag Recognition”).
Further, Ugradar et al. (Eye (Lond). August 2022, 36(8):1553-1559; hereinafter “Ugradar”) teaches a study (from clinical trials NCT01868997 and NCT03298867) (e.g., page 2, column 1, paragraph 2) in which patients with inactive/chronic TED were treated with teprotumumab, an IGF1R-inhibiting antibody that has been shown to significantly reduce the symptoms of TED (e.g., Abstract). As a conventional humanized monoclonal antibody, teprotumumab is comprised of 6 distinct CDR sequences, which includes 3 light-chain CDR sequences and 3 heavy-chain CDR sequences.
Based on the state of the art, a full complement of 6 CDRs are required for IGF1R antigen binding and a skilled artisan cannot envision the other CDR sequences based on a recitation of a single CDR that would bind and inhibit IGF1R to reduce the symptoms of inactive/chronic TED.
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for IGF1R antigen binding. However, instant claims 65 and 93 are inclusive of a partial structure of an antibody, which would not allow proper binding of the antibody to the IGF1R antigen to inhibit its function in order to treat TED. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in an antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 65 and 93 would need to recite the 6 CDRs (HCDR 1-3 and LCDR 1-3) in the antibody that bind IGF1R antigen, without variability in the sequences thereof.
Applicants can overcome the rejections of claims 65 and 93 by removing “and/or” between lines e and f, and replacing “and/or” with the word “and.”
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5-6, 9, 13-15, 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103 are rejected under 35 U.S.C. 102 (a)(1)/102 (a)(2) as being anticipated by WO 2021/041773 A1 (hereinafter “A773”), as evidenced by a substance search in SciFinder (SciFinder.org, Teprotumumab, https://scifinder-n.cas.org/searchDetail/substance/6a078911c7101a05f4044df5/substanceDetails).
Regarding instant claims 1-3, 5-6, 9, and 13-15, A773 taught a multicenter study comprising a method of treating individuals with chronic or inactive thyroid eye disease (TED) (instant claim 5), described as an autoimmune disorder which is typically associated with Graves’ hyperthyroidism (instant claim 2) (e.g., page 1, [001-002]), wherein the patient population has chronic or inactive TED (e.g., Example 31, page 62, [0295]), wherein the individuals of the patient population have a clinical activity score (CAS) of 0 or 1 (instant claim 3), wherein the patients have no significant progression or inflammatory symptoms within a year, which would anticipate the disease as inactive or chronic TED for at least 6 months (instant claim 6) (e.g., Example 31, page 62, [0296]), wherein the patients with inactive or chronic TED were administered an anti-insulin-like growth factor 1 receptor (IGF1R) study drug, wherein the IGF1R inhibitor was a 1) humanized IgG monoclonal antibody, i.e., dalotuzumab, 2) antigen binding fragment thereof, or 3) small molecule, i.e., picropodophyllin), as listed in A773 Table 1 (instant claim 1, instant claims 13-15) (e.g., Example 31, Table 1, pages 70-72; page 1, Abstract; page 25, [0183]). A773 also taught a method of treating or reducing the severity of inactive/chronic TED, comprising administering to a subject with inactive/chronic TED who has undergone prior treatment with an IGF1R inhibitor, and either did not respond to said prior treatment or responded to said prior treatment and then relapsed, an effective amount of an IGF1R-inhibiting antibody or small molecule that is not teprotumumab (instant claim 9) (e.g., page 22, [0166]; claims 33-37).
Regarding instant claims 54-55, 62, 65-69, 72, and 74-75, A773 taught a multicenter study comprising a method of improving the quality of life of individuals with inactive TED, wherein the individuals of the patient population have a clinical activity score (CAS) of 0 or 1 (instant claim 62) (e.g., Example 31, page 62, [0295-0296; Example 31, page 64, [0302]), which would anticipate the disease as inactive TED, comprising administering to the individuals with inactive TED an effective amount of teprotumumab (e.g., Example 31, page 62, [0295]). As evidenced by SciFinder, teprotumumab is comprised of the same CDR sequences as instant SEQ ID NO: 1-6 (instant claims 65-66) (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details).
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A773 further taught the average teprotumumab dosage administered to inactive TED patients in the multicenter study described above as 5-20 mg/kg (administered every 3 weeks, starting with an initial dose of 10 mg/kg, followed by a dose of 20 mg/kg for the remaining infusions) (instant claims 67-68) (e.g., Example 31, Table 1, page 70; page 69, [0326]), wherein the effects of the teprotumumab were measured via the Graves’ Ophthalmopathy Quality of Life (GO-QoL) questionnaire (e.g., Example 31, page 66, [0308]) and would naturally improve the quality of life of an individual with inactive thyroid eye disease by an increased score on the GO-QoL questionnaire (instant claim 54), wherein the method would naturally increase the score by at least 5 points (instant claim 55), wherein the teprotumumab naturally reduced proptosis by at least 1 mm (instant claim 69) and reduced diplopia by > 1 grade (instant claim 72) in the individuals with inactive TED (e.g., Example 31, page 80, [0383]). A773 also taught the exclusion criteria for subjects enrolled in the multicenter study described above, wherein those who were previously treated with teprotumumab (instant claim 74) or had previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery (instant claim 75) (e.g., Example 31, page 66, [0303]) were ineligible for study participation.
Regarding instant claims 78-79, 86, 93-97, 100, and 102-103, A773 taught a multicenter study comprising a method of improving the quality of life of individuals with chronic TED, wherein the patients had no significant progression or inflammatory symptoms within a year, which would anticipate the disease as chronic TED for 6 months or longer (instant claim 86) (e.g., Example 31, page 62, [0295-0296]; Example 31, page 64 [0302]), comprising administering to the individuals with chronic TED an effective amount of teprotumumab (e.g., Example 31, page 62, [0295]), which anticipates instant antibody comprising SEQ ID NO: 1-6 (instant claims 93-94) (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details), as evidenced by SciFinder.
A773 further taught the average teprotumumab dosage administered to chronic TED patients in the multicenter study described above as 5-20 mg/kg (administered every 3 weeks, starting with an initial dose of 10 mg/kg, followed by a dose of 20 mg/kg for the remaining infusions) (instant claims 95-96) (e.g., Example 31, Table 1, page 70; page 69, [0326]), wherein the effects of the teprotumumab were measured via the GO-QoL questionnaire (e.g., Example 31, page 66, [0308]) and would naturally improve the quality of life of an individual with chronic thyroid eye disease by an increased score on the GO-QoL questionnaire (instant claim 78), wherein the method would naturally increase the score by at least 5 points (instant claim 79), wherein the teprotumumab naturally reduced proptosis by at least 1 mm (instant claim 97) and reduced diplopia by > 1 grade (instant claim 100) in the individuals with chronic TED (e.g., Example 31, page 80, [0383]). A773 further taught the exclusion criteria for subjects enrolled in the multicenter study described above, wherein those who were previously treated with teprotumumab (instant claim 102) or had previously undergone orbital irradiation (instant claim 103) (e.g., Example 31, page 66, [0303]) were ineligible for study participation.
Double Patenting
Basis for nonstatutory double patenting:
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-6, 13, 15, 54-55, 62, 65-69, 72, 78-79, 86, 93-97, and 100 are rejected on the ground of anticipatory-type nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,600,787 (reference application; hereinafter “US787”), as evidenced by A773 and SciFinder. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
Regarding instant claims 1-3, 5-6, 13, 15, 62, and 86, US787 claims 1-8 and 11-13 are directed to a method of reducing proptosis in a subject with moderate-to severe inactive/chronic thyroid eye disease (TED), also known as Graves’ ophthalmopathy, as evidenced by A773 (e.g., page 2, [002]) (instant claims 2 and 5), wherein the subjects have a clinical activity score (CAS) of 0 or 1 (instant claims 3 and 62) and no inflammatory symptoms for at least one year (instant claims 6 and 86), comprising administering to the subject an effective amount of an insulin-like growth factor 1 receptor (IGF1R) inhibitor, wherein the IGF1R inhibitor is an IgG monoclonal antibody that specifically binds to IGF1R and inhibits the binding of IGF-I and IGF-II to IGF1R, including ganitumab, figitumumab, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, or istiratumab (instant claims 1, 13, and 15), as evidenced by A773 (e.g., Example 31, Table 1, List of Study Drugs, pages 70-72).
Regarding instant claims 54-55, 65-69, 72, 78-79, 93-97, and 100, the claims of US787 also comprised of a method of administering teprotumumab (intravenously at an initial dose of 10 mg/kg followed by doses of 20 mg/kg every three weeks) to subjects with inactive/chronic TED (instant claims 66-68 and 94-96) (e.g., claim 1 and claims 9-10 of US787), which anticipates the instant antibody comprising SEQ ID NO: 1-6 (instant claims 65 and 93) (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details), as evidenced by SciFinder, which will necessarily improve quality of life (i.e., reducing proptosis and diplopia) in subjects with inactive/chronic TED (instant claims 54-55, 69, 72, 78-79, 97, and 100) (e.g., claims 14-19 of US787).
Claims 1-3, 5-6, 13, 15, 54-55, 62, 65-69, 72, 74, 78-79, 86, 93-97, 100, and 102 are provisionally rejected on the ground of anticipatory-type nonstatutory double patenting as being unpatentable over claims 92-115 of copending U.S. Application No. 19/639,842 (reference application; hereinafter “A842”), as evidenced by A773 and SciFinder. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Regarding instant claims 1-3, 5-6, 13, 15, 62, and 86, A842 claims 92-107 are directed to a method of treating a subject with moderate-to severe inactive/chronic thyroid eye disease (TED), also known as Graves’ ophthalmopathy, as evidenced by A773 (instant claims 2 and 5) (e.g., page 2, [002]), wherein the subjects have been diagnosed with TED for at least 2 years (instant claims 6 and 86) and have a clinical activity score (CAS) of 0 or 1 (instant claims 3 and 62) in both eyes, comprising administering to the subject an effective amount of an insulin-like growth factor 1 receptor (IGF1R) inhibitor, wherein the IGF1R inhibitor is an IgG monoclonal antibody that specifically binds to IGF1R and inhibits the binding of IGF-I and IGF-II to IGF1R, including ganitumab and AVE1642 (instant claims 1, 13, and 15), as evidenced by A773 (e.g., Example 31, Table 1, List of Study Drugs, pages 70-72).
Regarding instant claims 54-55, 65-69, 72, 74, 78-79, 93-97, 100 and 102, the claims of A842 also comprised of a method of administering teprotumumab (intravenously at an initial dose of 10 mg/kg followed by doses of 20 mg/kg every three weeks) to subjects with inactive/chronic TED (instant claims 66-68 and 94-96) who had not been previously treated with an IGF1R inhibitor (i.e., first administration of an IGF1R inhibitor to the subject with inactive/chronic TED) (instant claims 74 and 102) (e.g., claims 108-110 of A842), which anticipates the instant antibody comprising SEQ ID NO: 1-6 (instant claims 65 and 93), as evidenced by SciFinder (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details), which will necessarily improve quality of life (i.e., reducing proptosis and diplopia) in subjects with inactive/chronic TED (instant claims 54-55, 69, 72, 78-79, 97, and 100) (e.g., claims 110-115 of A842).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 5-6, 13, and 15 are provisionally rejected on the ground of anticipatory-type nonstatutory double patenting as being unpatentable over claims 1, 5-8, 12-13, 15-16, and 22-23 of copending U.S. Application No. 18/978,929 (reference application; hereinafter “A929”), as evidenced by A773. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Regarding instant claims 1-3, 5-6, 13, and 15, the claims of A929 teach a method of treating moderate-to-severe inactive thyroid eye disease (TED), which is associated with chronic/long-term (i.e., 1 or more years) TED and is also known as Graves’ ophthalmopathy, as evidenced by A773 (e.g., page 2, [002]) (instant claims 2 and 5-6), to a patient in need thereof, wherein the patient with inactive TED has a clinical activity score (CAS) of 0 or 1 (instant claim 3) (e.g., claims 22-23 of A929), comprising administering to the patient an insulin-like growth factor 1 receptor (IGF1R) antagonist antibody (e.g., claim 1, claims 12-13, and claims 15-16 of A929), wherein the IGF1R antagonist antibody is a human IgG monoclonal antibody (that is not explicitly claimed to be teprotumumab) (instant claims 1, 13, and 15) (e.g., claims 5-8 of A929), as evidenced by A773 (e.g., Example 31, Table 1, List of Study Drugs, pages 70-72).
This is a provisional nonstatutory double patenting rejection because the patentably distinct claims have not in fact been patented.
Claims 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over
claims 1-7, 11, and 13-38 of U.S. Patent No. 12,358,993 (hereinafter “US993”)
claims 1-28 of U.S. Patent No. 12,209,130 (hereinafter “US130”)
claims 1-24 of U.S. Patent No. 11,208,489 (hereinafter “US489”)
claims 1-28 of US Patent No. 12,286,481 (hereinafter “US481”)
claims 1-11 of US Patent No. 11,208,490 (hereinafter “US490”)
in view of WO 2021/041773 A1 (reference application; hereinafter “A773”), as evidenced by SciFinder. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The patented claims are directed to a method of treating TED, comprised of administering an antibody that specifically binds to and inhibits IGF1R, wherein the antibody administered is teprotumumab and is administered intravenously at an initial dose of 10 mg/kg followed by doses of 20 mg/kg every three weeks to subjects with TED (instant claims 66-68 and instant claims 94-96) (e.g., claims 1-7, claim 11, claim 13, claims 19-27, and claim 36 of US993; claim 1, claims 5-20, and claims 25-28 of US130; claim 1 and claims 8-24 of US489; claims 1-27 of US481; claims 1-6 of US490). As evidenced by SciFinder, teprotumumab that is administered in the patented claims is comprised of the same CDR sequences as instant antibody comprising SEQ ID NO: 1-6 (instant claims 65 and 93) (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details). Performing the patented method will necessarily improve quality of life (i.e., reducing clinical activity score (CAS), proptosis, and diplopia) in subjects with TED (instant claims 54-55, 69, 72, 78-79, 97, and 100) (e.g., claims 14-18, claims 28-35, and claims 37-38 of US993; claims 1-4 and claims 21-24 of US130; claims 2-7 of US489; claim 28 of US481; claims 7-11 of US490).
The patented claims do not teach a method of treating individuals with inactive or chronic TED, wherein the individuals with inactive or chronic TED have not been previously treated with an IGF1R inhibitor and have not previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, but this is obvious in view of A773.
Regarding instant claims 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103, the teachings of A773 are described above. Specifically, A773 teaches a method of administering teprotumumab to treat inactive or chronic TED (e.g., Example 31, page 62, [0295]) in a patient population enrolled in a multicenter study, wherein the patients had no significant progression or inflammatory symptoms within a year, which would anticipate the disease as chronic TED for 6 months or longer (instant claim 86) (e.g., Example 31, page 62, [0295-0296]; Example 31, page 64 [0302]), and wherein those who were previously treated with teprotumumab or had previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery (e.g., Example 31, page 66, [0303]) were ineligible for study participation (instant claims 74-75 and 102-103).
It would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to practice the method of treating thyroid eye disease (TED) in a subject as claimed in US993/US130/US489/US481/US490, the method comprising administering to the subject an antibody that specifically binds to and inhibits insulin-like growth factor 1 receptor (IGF1R), with an inactive/chronic TED patient population that has not been previously treated with an IGF1R inhibitor, radiological treatments, or surgical treatments for their TED, because 1) active TED gradually progresses from an active (inflammatory) phase to an inactive/chronic (noninflammatory) phase, and 2) the inclusion of treatment-naive patients to a study eliminates the confounding effects of other medications or therapies used to treat inactive/chronic TED, as taught by A773 (e.g., page 1, [002]; pages 4-5, [017-018]). A PHOSITA would have been motivated to select the patient population with inactive/chronic TED in the method of treating thyroid eye disease (TED) in a subject, the method comprising administering to the subject an antibody that specifically binds to and inhibits IGF1R as taught by US993/US130/US489/US481/US490, with an inactive/chronic TED patient population that has not previously been treated with an IGF1R inhibitor or undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, because 1) in both active and inactive/chronic TED, orbital fibroblasts overexpress IGF1R (e.g., pages 2-3, [009]), and 2) there is a medical necessity for studies that analyze the effect of alternate therapies to treat inactive/chronic TED without interference from past treatments, as taught by A773 (e.g., page 5, [019]). Therefore, a PHOSITA would have a reasonable expectation of success of administering an IGF1R inhibitor to treatment-naive individuals with either active TED or inactive/chronic TED and reducing the symptoms seen in TED, such as proptosis and diplopia.
Thus, the claims of US993/US130/US489/US481/US490 would have been prima facie obvious over A773, especially in absence of evidence to the contrary.
Claims 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 112-119 of copending U.S. Application No. 18,548,484 (reference application; hereinafter “A484”) in view of WO 2021/041773 A1 (reference application; hereinafter “A773”), as evidenced by SciFinder. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
Copending claims 112-119 of A484 teach a method of treating a subject with inactive/chronic thyroid eye disease (TED), comprising administering to the subject a therapeutically effective amount of an antibody that binds to and inhibits insulin-like growth factor 1 receptor (IGF1R), wherein the IGF1R inhibitor reduces the clinical activity score (CAS) and the severity of proptosis and diplopia in a subject with inactive/chronic TED (instant claims 62, 69, 72, 97, and 100). A PHOSITA would understand that “improving the quality of life of an individual with TED” comprises reducing the signs and symptoms characteristic of TED (i.e., reducing the severity of proptosis and diplopia) after administration of anti-IGF1R antibody therapy, which would naturally improve the quality of life of an individual with inactive/chronic TED by an increased score on the GO-QoL questionnaire (instant claims 54 and 78), wherein the method would naturally increase the score by at least 5 points (instant claims 55 and 79).
A484 does not teach a method of administering teprotumumab at a dosage of 5 mg/kg to 50 mg/kg to a subject with TED who has not been previously treated with an IGF1R inhibitor or undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, but this is obvious in view of A773.
Regarding instant claims 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103, the teachings of A773 are described above. Specifically, A773 teaches a method of administering teprotumumab at a dosage of 5-20 mg/kg (administered every 3 weeks, starting with an initial dose of 10 mg/kg, followed by a dose of 20 mg/kg for the remaining infusions) (instant claims 66-68 and 94-96) (e.g., Example 31, Table 1, page 70; page 69, [0326]), to treat inactive or chronic (i.e., no significant progression or inflammatory symptoms within 1 year) TED (instant claim 86) (e.g., Example 31, page 62, [0295-0296]) in a patient population enrolled in a multicenter study, wherein those who were previously treated with teprotumumab or had previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery (e.g., Example 31, page 66, [0303]) were ineligible for study participation (instant claims 74-75 and 102-103). As evidenced by SciFinder, teprotumumab that is administered in the copending claims of A484 is comprised of the same CDR sequences as instant antibody comprising SEQ ID NO: 1-6 (instant claims 65 and 93) (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details).
It would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to practice the method of treating thyroid eye disease (TED) in a subject as claimed in A484, the method comprising administering to the subject an antibody that specifically binds to an inhibits insulin-like growth factor 1 receptor (IGF1R), with teprotumumab as the IGF1R administered to treat the TED patient population that has not been previously treated with an IGF1R inhibitor, radiological treatments, or surgical treatments for their TED, because 1) teprotumumab at a dosage of 5-20 mg/kg is a proven effective treatment for TED (e.g., pages 5-6, [017]; page 70, Example 31, Table 1), and 2) the inclusion of treatment-naive patients to a study eliminates the confounding effects of other medications or therapies used to treat inactive/chronic TED, as taught by A773 (e.g., page 1, [002]; pages 4-5, [017-018]). A PHOSITA would have been motivated to select the patient population with inactive/chronic TED in the method of treating thyroid eye disease (TED) in a subject, the method comprising administering to the subject an antibody that specifically binds to and inhibits IGF1R as taught by A484, with a TED patient population that is specifically treated with 5-20 mg/kg of teprotumumab and has not previously been treated with an IGF1R inhibitor or undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, because 1) teprotumumab is an approved IGF1R inhibitor for the treatment of TED (e.g., page 36, Example A, [0235]), and 2) there is a medical necessity for studies that analyze the effect of alternate therapies to treat inactive/chronic TED without interference from past treatments, as taught by A773 (e.g., page 5, [019]). Therefore, a PHOSITA would have a reasonable expectation of success in administering 5-20 mg/kg of teprotumumab to treatment-naive individuals with inactive/chronic TED and reducing the symptoms seen in TED, such as proptosis and diplopia.
Thus, the claims of A484 would have been prima facie obvious over A773, especially in absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably distinct claims have not in fact been patented.
Claims 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 41-59 of copending U.S. Application No. 19/233,919 (hereinafter “A919”) in view of WO 2021/041773 A1 (reference application; hereinafter “A773”), as evidenced by SciFinder. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The copending claims of A919 are directed to a method of treating TED, comprised of administering an antibody that specifically binds to and inhibits IGF1R, wherein the antibody administered is teprotumumab that is administered intravenously at an initial dose of 5-10 mg/kg followed by doses of 5-20 mg/kg every three weeks to subjects with inactive TED (instant claims 66-68 and 94-96) (e.g., claims 41-52, claims 54-55, claim 57, and claim 59 of A919). As evidenced by SciFinder, teprotumumab that is administered in the copending claims of A919 is comprised of the same CDR sequences as instant antibody comprising SEQ ID NO: 1-6 (instant claims 65 and 93) (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details). Performing the method of A919 will necessarily improve quality of life (i.e., reducing clinical activity score (CAS) and proptosis) in subjects with inactive TED (instant claims 54-55, 69, 78-79, 97) (e.g., claim 53, claim 56, and claim 58 of A919).
The copending claims of A919 do not teach a method of reducing diplopia in individuals with inactive or chronic TED, wherein the individuals with inactive or chronic TED have not been previously treated with an IGF1R inhibitor and have not previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, but this is obvious in view of A773.
Regarding instant claims 54-55, 62, 65-69, 72, 74-75, 78-79, 93-97, 100, and 102-103, the teachings of A773 are described above. Specifically, A773 teaches a method of reducing the severity of diplopia in a subject in a patient population with inactive/chronic TED enrolled in a multicenter study (instant claims 72 and 100) (e.g., Example 31, page 80, [0383]), wherein the patients with inactive/chronic TED had no significant progression or inflammatory symptoms within a year (instant claim 86) (e.g., Example 31, page 62, [0295-0296]; Example 31, page 64 [0302]), comprising administering to the subject an effective amount of teprotumumab (e.g., Example 31, page 62, [0295]), wherein those who were previously treated with teprotumumab or had previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery were ineligible for study participation (instant claims 74-75 and 102-103) (e.g., Example 31, page 66, [0303]).
It would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to practice the method of treating thyroid eye disease (TED) in a subject as claimed in A919, the method comprising administering to the subject an antibody that specifically binds to and inhibits insulin-like growth factor 1 receptor (IGF1R) as taught by A919, with an inactive/chronic TED patient population that has not been previously treated with an IGF1R inhibitor, radiological treatments, or surgical treatments for their TED, because 1) active TED gradually progresses from an active (inflammatory) phase to an inactive/chronic (noninflammatory) phase, and 2) the inclusion of treatment-naive patients to a study eliminates the confounding effects of other medications or therapies used to treat inactive/chronic TED, as taught by A773 (e.g., page 1, [002]; pages 4-5, [017-018]). There would have been reasonable expectation of success for a PHOSITA to include the patient population with inactive/chronic TED in the method of treating thyroid eye disease (TED) in a subject, the method comprising administering to the subject an antibody that specifically binds to and inhibits IGF1R as taught by A919, with an inactive/chronic TED patient population that has not previously been treated with an IGF1R inhibitor or undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, because 1) in both active and inactive/chronic TED, orbital fibroblasts overexpress IGF1R (e.g., pages 2-3, [009]), and 2) there is a medical necessity for studies that analyze the effect of alternate therapies to treat inactive/chronic TED without interference from past treatments, as taught by A773 (e.g., page 5, [019]). Therefore, a PHOSITA would have a reasonable expectation of success administering an IGF1R inhibitor to treatment-naive individuals with either active TED or inactive/chronic TED and reducing the symptoms seen in TED, such as proptosis and diplopia.
Thus, the copending claims of A919 would have been prima facie obvious over A773, especially in absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably distinct claims have not in fact been patented.
Claims 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-94, 97, 100, and 102-103 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over
claims 1-4, 15-17, 20, 22-27, 29-33, and 38 of copending U.S. Application No. 19/373,528 (hereinafter “A528”) in view of WO 2021/041773 A1 (reference application; hereinafter “A773”), as evidenced by SciFinder. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The copending claims of A528 are directed to a method of treating moderate to severe inactive TED in a patient in need thereof, comprised of administering a humanized IgG monoclonal antibody that specifically binds to and inhibits IGF1R, wherein the antibody administered is teprotumumab, which is administered subcutaneously at a dose of 1,575 mg to 1,750 mg once every two weeks to subjects with TED (instant claim 66) (e.g., claims of A528). As evidenced by SciFinder, teprotumumab that is administered in the claims of A528 is comprised of the same CDR sequences as instant antibody comprising SEQ ID NO: 1-6 (instant claims 65 and 93) (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details). Performing the method of A528 will necessarily improve quality of life (i.e., reducing clinical activity score (CAS), proptosis, and diplopia) in subjects with moderate to severe inactive TED (instant claims 54-55, 69, and 72) (e.g., claims 14-18, claims 28-35, and claim 37 of A528). A528 further taught the exclusion criteria for subjects enrolled in the multicenter study described above, wherein those with inactive TED who had previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery (instant claim 75) (e.g., claim 38 of A528) were ineligible for study participation.
A528 does not teach a method of improving the quality of life of individuals with chronic TED, comprising administering teprotumumab at a dosage of 5 mg/kg to 50 mg/kg to a subject with TED, wherein the individuals with chronic TED have not been previously treated with an IGF1R inhibitor, but this is obvious in view of A773.
Regarding instant claims 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103, the teachings of A773 are described above. Specifically, A773 teaches a method of administering teprotumumab at a dose of 5-20 mg/kg (administered every 3 weeks, starting with an initial dose of 10 mg/kg, followed by a dose of 20 mg/kg for the remaining infusions) (instant claims 65-69 and 93-96) (e.g., Example 31, page 62, [0295]) to patients with chronic TED who were enrolled in a multicenter study, wherein the patients had no significant progression or inflammatory symptoms within a year (instant claim 86) (e.g., Example 31, page 62, [0295-0296]; Example 31, page 64 [0302]), wherein the effects of the teprotumumab were measured via the GO-QoL questionnaire (e.g., Example 31, page 66, [0308]) and would naturally improve the quality of life of an individual with chronic TED by an increased score on the GO-QoL questionnaire (instant claim 78), wherein the method would naturally increase the score by at least 5 points (instant claim 79), wherein the teprotumumab naturally reduced proptosis by at least 1 mm (instant claim 97) and reduced diplopia by > 1 grade (instant claim 100) in the individuals with chronic TED (e.g., Example 31, page 80, [0383]). A773 further teaches the exclusion criteria for subjects with chronic TED enrolled in the multicenter study described above, wherein those who were previously treated with teprotumumab (instant claim 102) or had previously undergone orbital irradiation (instant claim 103) were ineligible for study participation (e.g., Example 31, page 66, [0303]).
It would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to combine the method of treating inactive thyroid eye disease (TED) in a subject as claimed in A528, the method comprising administering to the subject with inactive TED an antibody that specifically binds to and inhibits insulin-like growth factor 1 receptor (IGF1R), with the method of A773 comprised of administering 5-20 mg/kg teprotumumab to a chronic TED patient population that has not been previously treated with an IGF1R inhibitor, radiological treatments, or surgical treatments for their chronic TED, because 1) inactive TED is associated with chronic TED (i.e., chronic TED is the term used to describe the long-term/permanent sequelae of active TED) (e.g., page 1, [002]), 2) teprotumumab at a dosage of 5-20 mg/kg is a proven effective treatment for chronic TED (e.g., pages 5-6, [017]; page 70, Example 31, Table 1), and 3) including treatment-naive patients to a study eliminates the confounding effects of other medications used to treat chronic TED (e.g., page 1, [002]; page 6, [017]), as taught by A773. A PHOSITA would have been motivated to select the patient population with chronic TED in the method of treating inactive thyroid eye disease (TED) in a subject, the method comprising administering to the subject an antibody that specifically binds to and inhibits IGF1R as taught by A528, with the method of A773 comprised of administering 5-20 mg/kg of teprotumumab to subjects in a chronic TED patient population that has not previously been treated with an IGF1R inhibitor or undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, because 1) active/acute TED transitions into inactive TED, which is associated with long-term/chronic TED (e.g., page 1, [002]), and orbital fibroblasts overexpress IGF1R in both active/acute TED and inactive/chronic TED (e.g., pages 2-3, [009]), 2) teprotumumab is an approved IGF1R inhibitor for the treatment of TED (e.g., page 36, Example A, [0235]), and 3) there is a medical necessity for studies that analyze the effect of alternate therapies to treat inactive/chronic TED without interference from past treatments (e.g., page 5, [019]), as taught by A773. Therefore, a PHOSITA would have a reasonable expectation of success in administering 5-20 mg/kg of teprotumumab to treatment-naive individuals with inactive/chronic TED and reducing the symptoms seen in inactive/chronic TED, such as proptosis and diplopia.
Thus, the claims of A528 would have been prima facie obvious over the A773, especially in absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably distinct claims have not in fact been patented.
Claims 1-3, 5-6, 9, 13-15, 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 28-54 of copending U.S. Application No. 19/030,746 (reference application; hereinafter “A746”) in view of WO 2021/041773 A1 (reference application; hereinafter “A773”), as evidenced by SciFinder. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The copending claims of A746 are directed to a method of treating thyroid eye disease (TED) in a subject with TED, comprising reducing proptosis by 3 mm in the subject by administering to the subject an antibody that specifically binds to and inhibits insulin-like growth factor 1 receptor (IGF1R), wherein the antibody administered is a humanized IgG monoclonal antibody (that is not explicitly claimed to be teprotumumab) at a dose of 10-20 mg/kg (instant claims 1, 13, and 15) (e.g., claims 28-39 of A746). The claims of A746 also disclose a method of reducing the severity of diplopia in a subject with TED, comprised of administering to the subject an IGF1R inhibiting antibody, wherein the antibody is a humanized IgG monoclonal antibody that is administered subcutaneously or intravenously at a dose of 10-20 mg/kg (instant claims 67-68, 72, 95-96, and 100) (e.g., claims 28-39 of A746). Performing the copending methods will necessarily improve quality of life (i.e., reducing proptosis and diplopia) in subjects with TED (instant claims 54-55, 69, 78-79, and 97) (e.g., claim 28 and claims 40-52 of A746).
The copending claims of A746 do not teach 1) a method of treating an inactive/chronic TED patient population that has previously been treated with an IGF1R inhibitor, 2) a method of treating an inactive/chronic TED patient population comprising administering an IGF1R inhibitor to individuals with inactive/chronic TED, wherein the IGF1R inhibitor is a Fab, F(ab)2, a single-domain antibody, or a single chain variable fragment (scFv), 3) a method of treating an inactive/chronic TED patient population comprising administering teprotumumab at a dose of 5-50 mg/kg, wherein the individuals with inactive or chronic TED have not been previously treated with an IGF1R inhibitor and have not previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, but this is obvious in view of A773.
Regarding instant claims 1-3, 5-6, 9, and 13-15, the teachings of A773 are described above. Specifically, A773 teaches a multicenter study comprising a method of treating individuals with chronic or inactive TED (instant claim 5), described as an autoimmune disorder which is typically associated with Graves’ hyperthyroidism (instant claim 2) (e.g., page 1, [001-002]), wherein the patient population has chronic or inactive TED (e.g., Example 31, page 62, [0295]), wherein the individuals of the patient population have a clinical activity score (CAS) of 0 or 1 (instant claim 3), wherein the patients have no significant progression or inflammatory symptoms within a year (instant claim 6) (e.g., Example 31, page 62, [0296]), wherein the patients with inactive or chronic TED were administered an anti-insulin-like growth factor 1 receptor (IGF1R) study drug, wherein the IGF1R inhibitor was 1) a humanized IgG monoclonal antibody, i.e., dalotuzumab, 2) an antigen binding fragment thereof, or 3) a small molecule, i.e., picropodophyllin), as listed in A773 Table 1 (instant claim 1, instant claims 13-15) (e.g., Example 31, Table 1, pages 70-72; page 1, Abstract; page 25, [0183]). A773 also taught a method of treating or reducing the severity of inactive/chronic TED, comprising administering to a subject with inactive/chronic TED who has undergone prior treatment with an IGF1R inhibitor, and either did not respond to said prior treatment or responded to said prior treatment and then relapsed, an effective amount of an IGF1R-inhibiting antibody or small molecule that is not teprotumumab (instant claim 9) (e.g., page 22, [0166]; claims 33-37).
Regarding instant claims 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103, the teachings of A773 are described above. Specifically, A773 teaches a method of administering teprotumumab (i.e., an anti-IGF1R IgG monoclonal antibody) (e.g., page 70, Table 1, List of Study Drugs) at a dose of 5-20 mg/kg (administered every 3 weeks, starting with an initial dose of 10 mg/kg, followed by a dose of 20 mg/kg for the remaining infusions) (instant claims 66-68 and 9-96) (e.g., Example 31, page 62, [0295]) to treat inactive or chronic TED (e.g., Example 31, page 62, [0295]) in a patient population enrolled in a multicenter study, wherein the effects of the teprotumumab were measured via the GO-QoL questionnaire (e.g., Example 31, page 66, [0308]) and would naturally improve the quality of life of an individual with inactive/chronic TED by an increased score on the GO-QoL questionnaire (instant claims 54 and 78), wherein the method would naturally increase the score by at least 5 points (instant claims 55 and 79), wherein the patients had no significant progression or inflammatory symptoms within a year, which would anticipate the disease as chronic TED for 6 months or longer (instant claim 86) (e.g., Example 31, page 62, [0295-0296]; Example 31, page 64 [0302]), and wherein those who were previously treated with teprotumumab or had previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery (e.g., Example 31, page 66, [0303]) were ineligible for study participation (instant claims 74-75 and 102-103). As evidenced by SciFinder, teprotumumab that is administered in the claims of A773 is comprised of the same CDR sequences as instant antibody comprising SEQ ID NO: 1-6 (instant claims 65 and 93) (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details).
It would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to practice the method of treating thyroid eye disease (TED) in a subject as claimed in A746, the method comprising administering to the subject an antibody that specifically binds to and inhibits insulin-like growth factor 1 receptor (IGF1R) as taught by A746, with an inactive/chronic TED patient population that has been previously treated with an IGF1R inhibitor, wherein the subsequent treatment administered to the inactive/chronic TED patient population is an IGF1R inhibitor that is not teprotumumab, because 1) active TED gradually progresses from an active (inflammatory) phase to an inactive/chronic (noninflammatory) phase (e.g., page 1, [002]), and 2) not all TED patients benefit from treatment with teprotumumab (i.e., some TED patients may not respond to teprotumumab or may experience a relapse of their TED following treatment with teprotumumab), as taught by A773 (e.g., page 5, [019]). There would have been reasonable expectation of success for a PHOSITA to include the patient population with inactive/chronic TED in the method of treating thyroid eye disease (TED) in a subject, the method comprising administering to the subject an antibody that specifically binds to and inhibits IGF1R as taught by A746, with an inactive/chronic TED patient population that has previously been treated with an IGF1R inhibitor, wherein the subsequent treatment administered to the inactive/chronic TED patient population is an IGF1R inhibitor that is not teprotumumab, because 1) in both active and inactive/chronic TED, orbital fibroblasts overexpress IGF1R (e.g., pages 2-3, [009]), and 2) there is medical necessity for alternate therapies to treat inactive/chronic TED, as taught by A773 (e.g., page 5, [019]). Therefore, a PHOSITA would have a reasonable expectation of success administering an IGF1R inhibitor that is not teprotumumab to individuals with relapsed TED or inactive/chronic TED and reducing the symptoms seen in TED, such as proptosis and diplopia.
It would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to practice the method of treating TED in a subject as claimed in A746, the method comprising administering to the subject an antibody that specifically binds to and inhibits insulin-like growth factor 1 receptor (IGF1R) as taught by A746, with an inactive/chronic TED patient population that has not been previously treated with an IGF1R inhibitor, radiological treatments, or surgical treatments, wherein the inactive/chronic TED patient population is administered 5-20 mg/kg of teprotumumab, because 1) active TED gradually progresses from an active (inflammatory) phase to an inactive/chronic (noninflammatory) phase (e.g., page 1, [002]), 2) teprotumumab at a dosage of 5-20 mg/kg is a proven effective treatment for chronic TED (e.g., pages 5-6, [017]; page 70, Example 31, Table 1), and 3) including treatment-naive patients to a study eliminates the confounding effects of other medications used to treat inactive/chronic TED (e.g., page 1, [002]; page 6, [017]), as taught by A773. A PHOSITA would have been motivated to select the patient population with inactive/chronic TED in the method of treating inactive thyroid eye disease (TED) in a subject, the method comprising administering to the subject an antibody that specifically binds to and inhibits IGF1R as taught by A746, with the method of A773 comprised of administering 5-20 mg/kg of teprotumumab to subjects in an inactive/chronic TED patient population that has not previously been treated with an IGF1R inhibitor or undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, because 1) active/acute TED transitions into inactive/chronic TED, and IGF1R is overexpressed in orbital fibroblasts in both active/acute TED and inactive/chronic TED (e.g., page 1, [002]; pages 2-3, [009]), 2) teprotumumab is an approved IGF1R inhibitor for the treatment of inactive/chronic TED (e.g., page 36, Example A, [0235]), and 3) there is a medical necessity for studies that analyze the effect of alternate therapies to treat inactive/chronic TED without interference from past treatments (e.g., page 5, [019]), as taught by A773. Therefore, a PHOSITA would have a reasonable expectation of success in administering 5-20 mg/kg of teprotumumab to treatment-naive individuals with either active/acute TED or inactive/chronic TED and reducing the symptoms seen in inactive/chronic TED, such as proptosis and diplopia.
Thus, the claims of A746 would have been prima facie obvious over the A773, especially in absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably distinct claims have not in fact been patented.
Claims 1-3, 5-6, 9, 13-15, 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 234, 236, 238-242, 245-246, and 248-252 of copending U.S. Application No. 18/324,056 (reference application; hereinafter “A056”) in view of WO 2021/041773 A1 (reference application; hereinafter “A773”), as evidenced by SciFinder. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The copending claims of A056 are directed to a method of treating TED, comprised of administering an antibody that specifically binds to and inhibits IGF1R, wherein the antibody administered is ganitumab, figitumumab, cixutumumab, dalotuzumab, robatumumab, AVE1642, or istiratumab (instant claims 1, 13, and 15) (e.g., claims 238-241 and claims 248-251 of A056). A056 also discloses a method of treating TED, comprised of administering an IGF1R inhibiting antibody, wherein the antibody administered is teprotumumab (instant claims 66 and 94) (e.g., claims 242-243, claims 245-246, and claim 252 of A056). As evidenced by SciFinder, teprotumumab that is administered in the claims of A056 is comprised of the same CDR sequences as instant antibody comprising SEQ ID NO: 1-6 (instant claims 65 and 93) (e.g., SciFinder.org, Teprotumumab, CAS Registry Number: 1036734-93-6, Sequence Details).
The copending claims of A056 do not teach 1) a method of treating a patient population with inactive/chronic TED that has previously been treated with an IGF1R inhibitor, 2) a method of treating a patient population with inactive/chronic TED, the method comprising administering to an individual with inactive/chronic TED an IGF1R inhibitor, wherein the IGF1R inhibitor is a Fab, F(ab)2, a single-domain antibody, or a single chain variable fragment (scFv), and 3) a method of improving the quality of life of a patient population with inactive/chronic TED, the method comprising administering teprotumumab at a dose of 5-50 mg/kg, wherein the individuals with inactive or chronic TED have not been previously treated with an IGF1R inhibitor and have not previously undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, but this is obvious in view of A773.
Regarding instant claims 1-3, 5-6, 9, and 13-15, the teachings of A773 are described above. Specifically, A773 teaches a multicenter study comprising a method of treating individuals with chronic or inactive TED (instant claim 5), described as an autoimmune disorder which is typically associated with Graves’ hyperthyroidism (instant claim 2) (e.g., page 1, [001-002]), wherein the patient population has chronic or inactive TED (e.g., Example 31, page 62, [0295]), wherein the individuals of the patient population have a clinical activity score (CAS) of 0 or 1 (instant claim 3), wherein the patients have no significant progression or inflammatory symptoms within a year (instant claim 6) (e.g., Example 31, page 62, [0296]), wherein the patients with inactive or chronic TED were administered an anti-insulin-like growth factor 1 receptor (IGF1R) study drug, wherein the IGF1R inhibitor was 1) a humanized IgG monoclonal antibody, i.e., dalotuzumab, 2) an antigen binding fragment thereof, or 3) a small molecule, i.e., picropodophyllin), as listed in A773 Table 1 (instant claim 1, instant claims 13-15) (e.g., Example 31, Table 1, pages 70-72; page 1, Abstract; page 25, [0183]). A773 also taught a method of treating or reducing the severity of inactive/chronic TED, comprising administering to a subject with inactive/chronic TED who has undergone prior treatment with an IGF1R inhibitor, and either did not respond to said prior treatment or responded to said prior treatment and then relapsed, an effective amount of an IGF1R-inhibiting antibody or small molecule that is not teprotumumab (instant claim 9) (e.g., page 22, [0166]; claims 33-37).
Regarding instant claims 54-55, 62, 65-69, 72, 74-75, 78-79, 86, 93-97, 100, and 102-103, the teachings of A773 are described above. Specifically, A773 teaches a method of administering teprotumumab at a dose of 5-20 mg/kg (administered every 3 weeks, starting with an initial dose of 10 mg/kg, followed by a dose of 20 mg/kg for the remaining infusions) (instant claims 65-69 and 93-96) (e.g., Example 31, page 62, [0295]) to patients with inactive/chronic TED who were enrolled in a multicenter study, wherein the patients had no significant progression or inflammatory symptoms within a year (instant claim 86) (e.g., Example 31, page 62, [0295-0296]; Example 31, page 64 [0302]), wherein the effects of the teprotumumab were measured via the GO-QoL questionnaire (e.g., Example 31, page 66, [0308]) and would naturally improve the quality of life of an individual with inactive/chronic TED by an increased score on the GO-QoL questionnaire (instant claim 78), wherein the method would naturally increase the score by at least 5 points (instant claim 79), wherein the teprotumumab naturally reduced proptosis by at least 1 mm (instant claim 97) and reduced diplopia by > 1 grade (instant claim 100) in the individuals with chronic TED (e.g., Example 31, page 80, [0383]). A773 further teaches the exclusion criteria for subjects with inactive/chronic TED enrolled in the multicenter study described above, wherein those who were previously treated with teprotumumab (instant claim 102) or had previously undergone orbital irradiation (instant claim 103) were ineligible for study participation (e.g., Example 31, page 66, [0303]).
It would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to practice the method of treating thyroid eye disease (TED) in a subject as claimed in A056, the method comprising administering to the subject an antibody that specifically binds to and inhibits insulin-like growth factor 1 receptor (IGF1R) as taught by A056, with an inactive/chronic TED patient population that has been previously treated with an IGF1R inhibitor, wherein the subsequent treatment administered to the inactive/chronic TED patient population is an IGF1R inhibitor that is not teprotumumab, because 1) active TED gradually progresses from an active (inflammatory) phase to an inactive/chronic (noninflammatory) phase (e.g., page 1, [002]), and 2) not all TED patients benefit from treatment with teprotumumab (i.e., some TED patients may not respond to teprotumumab or may experience a relapse of their TED following treatment with teprotumumab), as taught by A773 (e.g., page 5, [019]). There would have been reasonable expectation of success for a PHOSITA to include the patient population with inactive/chronic TED in the method of treating thyroid eye disease (TED) in a subject, the method comprising administering to the subject an antibody that specifically binds to and inhibits IGF1R as taught by A056, with an inactive/chronic TED patient population that has previously been treated with an IGF1R inhibitor, wherein the subsequent treatment administered to the inactive/chronic TED patient population is an IGF1R inhibitor that is not teprotumumab, because 1) in both active and inactive/chronic TED, orbital fibroblasts overexpress IGF1R (e.g., pages 2-3, [009]), and 2) there is medical necessity for alternate therapies to treat inactive/chronic TED, as taught by A773 (e.g., page 5, [019]). Therefore, a PHOSITA would have a reasonable expectation of success administering an IGF1R inhibitor that is not teprotumumab to individuals with relapsed TED or inactive/chronic TED and reducing the symptoms seen in TED, such as proptosis and diplopia.
It would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to practice the method of treating TED in a subject as claimed in A056, the method comprising administering to the subject an antibody that specifically binds to and inhibits insulin-like growth factor 1 receptor (IGF1R) as taught by A056, with an inactive/chronic TED patient population that has not been previously treated with an IGF1R inhibitor, radiological treatments, or surgical treatments, wherein the inactive/chronic TED patient population is administered 5-20 mg/kg of teprotumumab, because 1) inactive TED is associated with chronic TED (i.e., chronic TED is the term used to describe the long-term/permanent sequelae of active TED) (e.g., page 1, [002]), 2) teprotumumab at a dosage of 5-20 mg/kg is a proven effective treatment for chronic TED (e.g., pages 5-6, [017]; page 70, Example 31, Table 1), and 3) including treatment-naive patients to a study eliminates the confounding effects of other medications used to treat inactive/chronic TED (e.g., page 1, [002]; page 6, [017]), as taught by A773. A PHOSITA would have been motivated to select the patient population with inactive/chronic TED in the method of treating inactive thyroid eye disease (TED) in a subject, the method comprising administering to the subject an antibody that specifically binds to and inhibits IGF1R as taught by A056, with the method of A773 comprised of administering 5-20 mg/kg of teprotumumab to subjects in an inactive/chronic TED patient population that has not previously been treated with an IGF1R inhibitor or undergone orbital irradiation, orbital decompression surgery, or strabismus surgery, because 1) active/acute TED transitions into inactive/chronic TED, and IGF1R is overexpressed in orbital fibroblasts in both active/acute TED and inactive/chronic TED (e.g., page 1, [002]; pages 2-3, [009]), 2) teprotumumab is an approved IGF1R inhibitor for the treatment of inactive/chronic TED (e.g., page 36, Example A, [0235]), and 3) there is a medical necessity for studies that analyze the effect of alternate therapies to treat inactive/chronic TED without interference from past treatments (e.g., page 5, [019]), as taught by A773. Therefore, a PHOSITA would have a reasonable expectation of success in administering 5-20 mg/kg of teprotumumab to treatment-naive individuals with either active/acute TED or inactive/chronic TED and reducing the symptoms seen in inactive/chronic TED, such as proptosis and diplopia.
Thus, the claims of A056 would have been prima facie obvious over the A773, especially in absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably distinct claims have not in fact been patented.
Conclusion
No claims are currently allowed.
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/MALIA NICOLE GREEN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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