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
Claims 1-17 are pending.
Claim 17 is new.
Claims 5, 10-12 and 16 are amended.
Claims 1-17 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The U.S. effective filing date of all claims under examination is therefore set at Filing Date 09/30/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on Pg. 7 Paragraph [0043]:
https://extranet.who.int/soinn/mod/page/view.php?id=137&inn_n=10932
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 https://, http://, www., or other browser-executable code. See MPEP § 608.01.
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.
Claims 1-10, 12-13, and 15-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCT04078386 (Record History Version 1 Date Submitted 2019-09-01), as evidenced by PRNewswire (RemeGen Ltd Announcement Nov 15, 2019), Dhillon (Drugs 2021, 81:1671–1675; Published online: 31 August 2021) and International Nonproprietary Names for Pharmaceutical Substances (INN) (Telitacicept in WHO DRUG INFORMATION, VOL.33, NO.3, Year 2019, P.689; provided on the IDS submitted on 03/25/2024 and 11/14/2024).
NCT04078386 teaches a study using TACI-antibody fusion protein (RC18) administered via injection for the treatment of subjects with primary Sjögren's syndrome (Brief Title and Official Title). They teach that RC18 is a recombinant human B lymphocyte stimulator receptor and immunoglobulin G (IgG ) Fc fusion protein (Official Title). They also teach that the study includes administering placebo or administering TACI-Fc fusion protein to subjects at a dose of 160 mg or at a dose of 240 mg (Arms and Interventions), which is equivalent to an “effective amount” of TACI-Fc. They further teach that subjects received 160 mg or 240 mg doses at a frequency of once every week via subcutaneous injection for a total of 24 times (Arms and Interventions; Assigned Interventions).
As evidenced by PRNewswire, RC18 is also known as telitacicept, and it is a novel recombinant TACI-Fc fusion protein developed to treat autoimmune diseases. PRNewswire also teaches that RC18 works by binding to two cell-signaling molecules, B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) and by only affecting mature B cells, RC18 has minimal impact on early and memory B cells, which are important for normal body immune function (paragraph sixth “About RC18 (telitacicept)”). PRNewswire further teaches that RC18 was being studied in several late-stage clinical trials across autoimmune diseases (paragraph sixth). Therefore, PRNewswire gives evidence and confirms that the RC18 of NCT04078386 is also known as Telitacicept.
Further, as evidenced by Dhillon, Telitacicept (Tai'ai®) comprises an extracellular domain of the human transmembrane activator or calcium-modulating cyclophilin ligand-interactor (TACI) receptor fused to a human immunoglobulin G fragment crystallizable (Fc) domain (Abstract and Pg. 1672 column right paragraph second). Dhillon also teaches that Telitacicept binds to and neutralizes the activity BLyS and the proliferation-inducing ligand APRIL, thereby suppressing the development and survival of plasma cells and mature B cells (Abstract). They further teach that telitacicept received its first approval in China for the treatment of patients with active SLE and the clinical study of telitacicept in Sjögren's syndrome was underway in China (Abstract, Pg. 1672 Timeline Diagram at top of the page and Pg. 1674 Table at top of the page, Row seven). They also further teach that the pharmacokinetics of telitacicept was evaluated after a single subcutaneous dose in a phase 1 study (Pg. 1672 column right paragraph “2.2 Pharmacokinetics”). Therefore, Dhillon gives evidence and confirms that the TACI-antibody fusion protein named RC18 of NCT04078386 and PRNewswire is also known as Telitacicept, and Dhillon further confirms that RC18 comprises an extracellular domain of human TACI receptor that can bind BLyS and APRIL and is fused to a human immunoglobulin G fragment crystallizable (Fc) domain.
Furthermore, as evidenced by International Nonproprietary Names for Pharmaceutical Substances (INN), residues 1-106 of telitacicept consists of the human TACI extracellular domain fragment (residues 13 to 118) that is fused to human IgG1 (227 C-terminal residues; γ1-chain Fc fragment) from residues 107-333 (Pg. 689). INN also teaches that the amino acid sequence of telitacicept is given by the sequence as shown below:
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489
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When the sequence of telitacicept as disclosed in the INN was compared with instant SEQ ID NO: 1, the two sequences were at a 100% match with each other from residues 1-106 of telitacicept (see Alignment 1 below).
Alignment 1: Alignment of instant SEQ ID NO: 1 (top sequence) with the amino acid sequence of Telitacicept as provided on Pg. 689 of the International Nonproprietary Names for Pharmaceutical Substances (INN) WHO DRUG INFORMATION, VOL.33, NO.3, Year 2019 (bottom sequence).
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In addition, when telitacicept as disclosed in the INN was compared with instant SEQ ID NO: 2, the two sequences were found to have 96.5% best local similarity for residues 107-333 of telitacicept which is the portion corresponding to the fragment of human immunoglobulin constant region (see Alignment 2 below). It was noted that the mismatches are located on amino acid positions 3, 8, 14, 15, 17, 110, 111 and 173 of instant SEQ ID NO: 2. Specifically, the mismatches corresponded to P3T, L8P, L14A, L15E, G17A, A100S, P11 S and A173T substitutions. These substitutions are exactly those recited in instant claim 6 for the substitutions that are to be made on instant SEQ ID NO: 2.
Alignment 2: Alignment of instant SEQ ID NO: 2 (top sequence) with the amino acid sequence of Telitacicept as provided on Pg. 689 of the INN (WHO DRUG INFORMATION, VOL.33, NO.3, Year 2019; bottom sequence).
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287
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Further when telitacicept as disclosed in the INN was compared with instant SEQ ID NO: 3, the two sequences were exactly identical from residues 107-333 of telitacicept which is the portion corresponding to the fragment of human immunoglobulin constant region (see Alignment 3 below).
Alignment 3: Alignment of instant SEQ ID NO: 3 (top sequence) with the amino acid sequence of Telitacicept as provided on Pg. 689 of the INN (WHO DRUG INFORMATION, VOL.33, NO.3, Year 2019; bottom sequence).
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Moreover, when the amino acid of telitacicept as disclosed in the INN was compared with the TACI-Fc fusion protein recited in instant claim 8 which has an amino acid sequence set forth in instant SEQ ID NO: 4, it was found that they are an exact match to each other (see Alignment 4 below).
Alignment 4: Alignment of instant SEQ ID NO: 4 (top sequence) with the amino acid sequence of Telitacicept as provided on Pg. 689 of INN (WHO DRUG INFORMATION, VOL.33, NO.3, Year 2019 ;bottom sequence).
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Therefore, the clinical trial study of TACI-antibody fusion protein (RC18) administered via subcutaneous injection at a dose of 160 mg or at a dose of 240 mg for the treatment of subjects with primary Sjögren's syndrome at a frequency of once every week for a total of 24 times taught by NCT04078386 anticipates the instant claims above.
With regards to claims 12 and 17, any or every dose that is administered to a patient at a dose of 160 mg or 240 mg as taught by NCT04078386 would be a single dose administered at the time of administration, which therefore meets the limitation of “the TACI-Fc fusion protein is administered at a single dose of 160 to 240 mg”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-17 are rejected under 35 U.S.C. 103(a) as being unpatentable over NCT04078386 (Record History Version 1 Date Submitted 2019-09-01) as applied to claims 1-10, 12-13, and 15-17 and in further view of PRNewswire (RemeGen Ltd Announcement Nov 15, 2019), Dhillon (Drugs 2021, 81:1671–1675; Published online: 31 August 2021), International Nonproprietary Names for Pharmaceutical Substances (INN) (Telitacicept in WHO DRUG INFORMATION, VOL.33, NO.3, Year 2019, P.689; provided on the IDS submitted on 03/25/2024 and 11/14/2024) and Bird et al. (Curr Opin Rheumatol. 2015 September; 27(5): 461–467).
The teachings of NCT04078386, have been described in the 102 rejection above.
NCT04078386 does not specifically teach wherein the TACI-Fc fusion protein is administered at a single dose of about 0.1 to 10 mg/kg; or wherein the TACI-Fc fusion protein is administered at a single dose of 160 to 240 mg, 2-4 times at intervals of one month.
However, these deficiencies are made up by optimizations of the method as taught by NCT04078386 and by the teachings of PRNewswire, Dhillon, INN, and Bird et al.
Teachings of PRNewswire, Dhillon, and INN are discussed above.
Bird et al. teaches and confirms that both SLE and Sjogren’s syndrome are autoimmune diseases that share pathogenic functions of B cells (Abstract and Introduction).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a method for treating Sjogren’s syndrome comprising administering a therapeutically effective amount of a TACI-Fc fusion protein to a patient with primary Sjogren's syndrome named RC18 as taught by NCT04078386, wherein the RC18 is also known as telitacicept and comprises a TACI-Fc fusion protein comprising: (i) a TACI extracellular region or a fragment thereof binding to Blys and/or APRIL; and (ii) a fragment of human immunoglobulin constant region as evidenced by PRNewswire, Dhillon and INN, and wherein the fragment of human immunoglobulin constant region is IgG1 as evidenced by INN, and wherein the amino acid sequence of telitacicept (RC18) is as evidenced by INN, and to optimize the administered dose and dosing schedule as taught by NCT04078386 because NCT04078386 teaches that RC18 was studied in patients with primary Sjögren's syndrome in a clinical trial, PRNewswire teaches that whilst RC18 is able to bind to the two cell-signaling molecules of BlyS and APRIL thereby only disrupting mature B cells to have minimal impact on early and memory B cells thus preserving normal body immune function (paragraph sixth “About RC18 (telitacicept)”), Dhillon teaches that RC18 (Telitacicept) was developed for the treatment of B cell-mediated autoimmune diseases and obtained approval in China for the treatment of patients with active SLE (Abstract) and Bird et al. teaches and confirms that both SLE and Sjogren’s syndrome are autoimmune diseases that share pathogenic functions of B cells (Abstract and Introduction), thus further giving support for the use of RC18, that has shown success in the treatment of SLE, for the treatment of patients with Sjogren’s syndrome. This is an example of (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to claim 11, NCT04078386 teaches that TACI-Fc fusion protein is administered at a dose of 160 mg or 240 mg. If the average weight of adult men in the U.S is around 91kg, and if given the dose is 160 mg, this is equivalent to a dose of 1.76 mg/kg, while the dose of 240 mg is equivalent to a dose of 2.64 mg/kg. Similarly, if the average weight of adult women in the U.S is around 77 kg, and if the given dose is 160 mg, this is equivalent to 2.08 mg/kg, while the dose of 240 mg is equivalent to 3.12 mg/kg. Therefore, the recited method wherein the TACI-Fc fusion protein is administered at a single dose of about 0.1 to 10 mg/kg is thus met since the doses taught by NCT04078386 of 160 mg or 240 mg are equivalent to 1.76 mg/kg or 2.64 mg/kg respectively for an average weight male, and also equivalent to 2.08 mg/kg or 3.12 mg/kg respectively for an average weight female. These doses fall within the range of 0.1 to 10 mg/kg as recited in instant claim 11. Further, it would be conventional and routine for one to perform a combined method comprising injecting just any subject with Sjögren's syndrome with the TACI-antibody fusion protein of NCT04078386, PRNewswire, Dhillon and INN at various dosages and dosing schedules to a subject with Sjogren’s syndrome as taught by NCT04078386, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” In the instant case, given the known dosage of RC18 TACI-Fc fusion protein to treat subjects with primary Sjögren's syndrome as taught by NCT04078386, it is well within the level of the ordinary skilled artisan to adjust the administration dosages for optimal therapeutic efficacy and safety, and to arrive at the administered dosage ranges as instantly claimed, where the TACI-antibody fusion protein (RC18) is expected to provide therapeutic Sjogren's syndrome treatment. Furthermore, varying dosage amounts of the administered therapeutic TACI-antibody fusion protein of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered therapeutic fusion protein. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to claim 14, NCT04078386 teaches once a week administration of RC18 by subcutaneous injection to patients with primary Sjögren's for 24 weeks. Therefore, it would be conventional and routine for one to perform a combined method comprising injecting just any subject with Sjögren's syndrome with the TACI-antibody fusion protein of NCT04078386, also known as RC18 or telitacicept as evidenced by PRNewswire, Dhillon and INN, at various dosages and dosing schedules to a subject with Sjogren’s syndrome as taught by NCT04078386, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” In the instant case, given the known dosages and dosage schedule of RC18 TACI-Fc fusion protein to treat subjects with primary Sjögren's syndrome as taught by NCT04078386, it is well within the level of the ordinary skilled artisan to adjust the timing of dosage administration for optimal therapeutic efficacy and safety, and to arrive at the timing of dosage administration as instantly claimed, where the TACI-antibody fusion protein (RC18) is expected to provide therapeutic Sjogren's syndrome treatment. Furthermore, varying dosage schedules of the administered therapeutic TACI-antibody fusion protein of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered therapeutic fusion protein. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yie-Chia Lee (Tonya) whose telephone number is (571)272-0123. The examiner can normally be reached Monday - Friday 7.30a - 3.30p Eastern Time Zone.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642