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 .
Claim Status
Claim 16 has been cancelled and claims 11-13 have been amended as requested in the preliminary amendment filed on 04/26/2023. Following the amendment, claims 1-15 are pending in the instant application.
Claims 1-15 are under examination in the instant office action.
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. However, it is noted that the claim to foreign priority has not been perfected, as no English copy of the foreign priority document has been provided.
Claims 1-15 have an effective filing date of August 9, 2022 corresponding to PCT/CN2022/111112, as the claim to foreign priority has not been perfected.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/26/2023, 03/05/2024, 07/30/2024, 10/30/2024, and 02/17/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements 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 at 0042 of the corresponding PGPub. 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://, www, or other browser-executable code. See MPEP § 608.01.
Claim Interpretation
With regard to claims 4-6, it is noted that recited positions for mutation are understood as being “sequence numbering” as defined in Paragraph 0043 of the instant specification, wherein the numbering is based on reference SEQ ID NO: 2. In other words, a mutation at position 3 refers to a mutation at the third amino acid residue of SEQ ID NO: 2.
Claim Objections
Claim 1 is objected to because of the following informalities: the claim currently reads "a TACI extracellular region or a fragment thereof binding to Blys and/or APRIL", but it is noted that in [0036] of the specification "Blys" is defined and is represented as "BLys"; the representation of terms/abbreviations in the claims should be consistent with the specification.
Claim 4 is objected to because of the following informalities: the claim currently reads "one or more modifications of amino acid at positions" but should read "one or more modifications of amino acids at positions".
Claim 5 is objected to because of the following informalities: the claim currently reads "deletion or insertion of amino acid", but should read "deletion or .
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-14 are 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.
With regard to claim 1, it is noted that the claim currently reads "a TACI extracellular region or a fragment thereof binding to Blys and/or APRIL". As currently presented, it is unclear as to if the TACI extracellular domain is constantly bound to Blys and/or APRIL or if the TACI extracellular domain has the ability to bind Blys and/or APRIL. Additionally, it is noted that based on the instant specification there are multiple possible interpretations with regard to “APRIL”. Paragraph 0036 of the instant specification defines “APRIL” (a proliferation inducing ligand) as follows: the term refers to “a tumor necrosis factor (TNF) analogue, which can stimulate the proliferation of primitive B cells and T cells in the body, promote the accumulation of B cells and increase its content in spleen. APRIL can specifically bind to TACI and BCMA, and the binding can prevent APRIL from binding to B cells and inhibit the proliferative response of primitive B cells stimulated by APRIL. Moreover, APRIL can compete with BLys for binding to receptors BCMA and TACI”. This definition could be interpreted to be any TNF with the recited function(s), or just one species of the family. As such, there could be multiple interpretations of the claim as currently presented, rendering the claim indefinite. Claims 2-14 are included in this rejection as they all depend from and/or incorporate claim 1.
With regard to claims 2-3, 7, and 9, the claims are considered to be indefinite due to their recitation of “an amino acid sequence set forth in” the recited SEQ ID NOs. The “an amino acid sequence” language makes it unclear as to if the intended scope with reference to the SEQ ID NOs. is meant to be the full-length sequences or any fragments thereof. As such, the recitation of “an amino acid sequence” language renders the claims indefinite. Claims 4-6, 8, and 10 are included in this rejection as they all depend from and/or incorporate claims 2-3, 7, or 9.
Regarding claim 11, the phrase "more preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 12, the term “about” is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, nor is the term explicitly defined in the instant specification, and 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.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-15 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.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The claims are drawn to a genus of TACI-Fc fusion proteins; more specifically TACI-Fc fusion proteins that may comprise truncated TACI extracellular domains (i.e., TACI extracellular domain fragments; see claim 1) and/or mutated immunoglobulin constant domains (see claims 3-6). The instant specification provides no specific guidance on/examples of TACI extracellular domain truncations that are functional outside of the truncation that corresponds to instant SEQ ID NO: 1 (see Paragraph 0009). Similarly, the instant specification provides no specific guidance on/examples of mutated immunoglobulin constant regions outside of the specific mutations of P3T, L8P, L14A, L15E, G17A, A110S, P111S, and A173T relative to instant reference SEQ ID NO: 2; it is specifically noted that instant SEQ ID NO: 3 is the exemplary immunoglobulin constant region which comprises all of the above-listed mutations (see Paragraphs 10-13). As such, the only TACI-Fc protein sufficiently described by the instant specification is that of instant SEQ ID NO: 4, corresponding to Telitacicept (see Paragraphs 0015-0016).
However, even though Applicant has disclosed one species of TACI-Fc fusion protein, Applicant is claiming a large and structurally diverse genus of TACI-Fc fusion proteins, each of which may comprise one of many possible TACI extracellular region fragments/truncations in combination with a mutated immunoglobulin constant domain. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically which combinations of TACI extracellular domain fragments and mutated immunoglobulin constant regions would yield TACI-Fc fusion proteins that are capable of binding Blys and/or APRIL and exerting therapeutic effects in cases of IgA nephropathy. Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
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, reduction to drawings, 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 applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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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. As previously indicated, Applicant has disclosed only one species within the genus claimed. Given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of said single species is not sufficiently representative of the entire genus.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of TACI extracellular region fragments and/or mutated immunoglobulin constant domains that would allow them to retain functionality. It is well-known in the art that protein chemistry is highly unpredictable. As such, absent a description of the at least minimal structural features correlating with (i) a functional ability of TACI extracellular region fragments to bind Blys and/or APRIL and (ii) mutated immunoglobulin constant regions that retain functionality, which are shared by members of a genus commonly sharing said functions, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which TACI extracellular region fragments and mutated immunoglobulin constant regions may be combined such that the resultant TACI-Fc fusion proteins retain the ability to bind Blys and/or APRIL and exert therapeutic effects.
Although screening techniques can be used to isolate/identify truncated TACI extracellular domains and mutated immunoglobulin constant domains, and subsequently TACI-Fc fusion proteins thereof, that retain the ability to bind Blys and/or APRIL and exert therapeutic functions, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
Accordingly given the difficulty associated with predicting TACI extracellular region fragments and mutated immunoglobulin constant regions that may be combined such that the resultant TACI-Fc fusion proteins retain the ability to bind Blys and/or APRIL and exert therapeutic effects, and given the lack of particularity with which the claimed TACI-Fc fusion proteins are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
Claims 1-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating IgA nephropathy in patients diagnosed with IgA nephropathy with tested, functional TAC1 extracellular domain fusion proteins, does not reasonably provide enablement for preventing with any agent or treatment thereof with just any mutant/truncate of a known fusion protein. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The Breadth of the Claims
Claims 1 and 15 each recite “[a] method for treating IgA nephropathy” generally comprising administering a therapeutically effective amount of a TACI-Fc fusion protein to a subject in need thereof. Paragraph 0046 of the instant specification indicates that the term "treatment" used in the present invention is related to a given disease or condition, including but not limited to: inhibiting the disease or symptom, such as preventing the development of the disease or symptoms; alleviating the disease or symptoms, such as causing the regress of the disease or symptoms; or alleviating the symptoms caused by the disease or symptoms, such as alleviating, preventing or treating the symptoms caused by the disease or symptoms (emphasis added). As such, claims 1 and 15 are drawn to the prevention of IgA nephropathy, the full scope of which is not enabled. It is further noted that claims 1 and 15 are generally drawn to methods of treatment comprising administering the TACI-Fc fusion protein, and as presented are drawn to any mode of administration. It is further noted that claim 13, recites that “the TACI-Fc fusion protein is administered by subcutaneous injection, intramuscular injection, oral or intravenous administration”. However, it is noted that not all routes of administration are appropriate for protein-based therapeutics, and as such the full scope of claims 1, 13, and 15 are not enabled.
Further with regard to claim 1, the claim also recites “a TACI extracellular region or a fragment thereof”. Thus, claim 1 is drawn to modification of the TACI extracellular region generally by truncation; any and all possible mutations/truncations are useful or tolerated by a proteins and as such, it is unclear as to which possible truncations would still yield a TACI fragment capable of functioning as recited in the claim. Therefore, the full scope of claim 1 regarding TACI extracellular region fragments is not enabled.
With regard to claims 3-5, the claims are drawn generally to mutated immunoglobulin constant domains; claim 3 recites immunoglobulin constant domains having “at least 90% identity to SEQ ID NO: 2” and claim 4 recites “the human immunoglobulin region constant region comprises one or more modifications of amino acid at positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO: 2. Claims 5 narrows the types of mutations allowed at the positions recited in claim 4. It is noted, that any and all possible mutations are useful or tolerated by a proteins and as such, it is unclear as to which possible mutations, how many possible mutations, and what combinations of mutations would still yield an immunoglobulin constant region still capable of functioning. Therefore, the full scope of claims 3-5 regarding immunoglobulin constant region mutations is not enabled.
The State of the Prior Art/Level of Predictability in the Art
The pathophysiology of IgA nephropathy (IgAN) is complicated and multi-faceted. As disclosed by Suzuki et. al. (J. Am. Soc. Nephrol., 2011, 22, 1795-1803), four processes come together to induce renal injury that culminates in IgAN: aberrant glycosylation of IgA1, synthesis of antibodies directed against galactose-deficient IgA1, binding of the galactose-deficient IgA1 by the anti-glycan/glycopeptide antibodies to form immune complexes, and accumulation of these complexes in the glomerular mesangium to initiate renal injury (Page 1795, Column 2, Second Paragraph). Suzuki et. al. describe the four processes involved in pathogenesis of IgA nephropathy: (i) hereditary increase in galactose-deficient circulating IgA1; (ii) circulating antibodies directed against galactose-deficient IgA1; (iii) formation of pathogenic IgA1-containing immune complexes; and (iv) mesangial deposition of IgA1-containing immune complexes, cell activation, and initiation of glomerular injury (Pages 1796-1799). Additionally, Table 1 further indicates that within each process there may or may not be environmental factors and/or genetic factors that may be involved. Potential therapeutic interventions are also proposed on Page 1801; no mention of disease prevention is ever provided. Suzuki et. al. conclude that IgAN is an autoimmune renal disease arising from consequences of increased circulating levels of IgA1 with galactose-deficient hinge-region O-glycans; however, this glycosylation aberrancy alone is not sufficient to induce nephritis(Page 1801, Columns 2-3, Conclusions). For the clinical manifestation of renal injury, several additional hits are required, including synthesis of circulating antibodies directed against the aberrantly glycosylated O-linked hinge-region glycans to form immune complexes, accumulation of the complexes in the mesangium, and activation of mesangial cell; genetic factors apparently influence the expression of these hit mechanisms and the elucidation of the pathogenesis of IgAN provides an opportunity to develop a disease-specific therapy that heretofore has been missing. Thus, Suzuki et. al. suggest that therapeutic options for the treatment of IgA nephropathy have generally been limited and the multi-faceted pathology may require various approaches for effective therapeutics.
To date, there is no definitive evidence that IgA nephropathy can effectively be prevented.
With regard to protein/peptide modifications, the art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, conservative replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
With respect to the use of peptides in the treatment of a disease such as cancer, the state of the art at the time of filing was such that it was unpredictable whether or not a peptide would function therapeutically. Their functionality depends, in part, on whether or not they reach their intended target in a sufficient quantity as to cause a therapeutic effect. Mendoza (Arch. Immunol. Ther. Exp., Vol. 53, Pg. 47-60, 2005) teaches that peptides derived from larger molecules that are important modulators of apoptosis are frequently becoming leads for the development of anticancer therapeutics (Pg. 48, Column 2, Paragraph, first partial). However, they also state that natural peptides have low bioavailability and short half-life in the mammalian circulation system, while synthetic peptides have potential cytotoxicities (Pg. 57, Column 1, Paragraph, last full). Due to these characteristics, systematic testing in in vivo as well as in vitro settings must be done rigorously to verify peptide applications in the clinic (Pg. 57, Column 1, Paragraph, last full). Taken together, barring experimental evidence, no peptide can merely be assumed to function in the treatment of a disease, for example cancer, in vivo just because it functions as an inhibitor in vitro.
With respect to the use of peptides in the treatment of disease, the state of the art at the time of filing was such that it was unpredictable whether or not a peptide would function therapeutically in vivo. Their functionality depends, in part, on whether or not they reach their intended target in a sufficient quantity as to cause a therapeutic effect. Mendoza (Arch. Immunol. Ther. Exp., Vol. 53, Pg. 47-60, 2005) teaches that peptides derived from larger molecules that are important modulators of apoptosis are frequently becoming leads for the development of anticancer therapeutics (Pg. 48, Column 2, Paragraph, first partial). However, they also state that natural peptides have low bioavailability and short half-life in the mammalian circulation system, while synthetic peptides have potential cytotoxicities (Pg. 57, Column 1, Paragraph, last full). Due to these characteristics, systematic testing in in vivo as well as in vitro settings must be done rigorously to verify peptide applications in the clinic (Pg. 57, Column 1, Paragraph, last full).
With regard to routes of administration, the teachings of Mendoza are echoed by Vlieghe (US2013/0108548, published 05/02/2013) who teaches that principal limitations attributed to peptides include low oral bioavailability, their short half-life due to rapid breakdown by enzymes in digestive system and blood plasma, and their rapid elimination from circulating blood by the liver and kidneys (0179).
Reilly (Clin. Pharmacokinet., Vol. 32, No. 4, Pg. 313-323, 1997) teaches that the normal physiological handling of ingested proteins is degradation by proteases in the stomach and intestine (Pg. 313, Paragraph, second). At most, antibody Fab and F(ab’)2 retain some activity locally in the gastrointestinal tract (Pg. 313, Paragraph, second). Indeed the field administers antibodies intravenously since orally administered antibody would become degraded and inactivated by proteases in the stomach and intestine (Pg. 314, Column 1, Paragraph, second). They state that there appears to be little systemic absorption of intact immunoglobulins through the human gastrointestinal tract (Pg. 318, Column 2, Paragraph, second). Taken together, the art demonstrates that it is unpredictable that sufficient antibody will enter system circulation via an oral administration route in order to treat liver cancer.
In view of the above, barring experimental evidence, no peptide/immunoglobulin-based therapeutic can merely be assumed to function in vivo when administered by just any route. This is unpredictable for any given peptide drug. Rather, each route must be verified through testing. To determine at a later date which routes function and which do not is undue experimentation. Thus, as broadly as currently written, the instant claims above are not enabled to their full scope.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
It is noted that the only working example provided by Applicant is Example 1 on Pages 9-15 of the instant specification; it is specifically noted that Example 1 is drawn to the treatment of patients confirmed as having IgA nephropathy. As such, the only direction/working example provided by the instant specification only pertains to treating patients diagnosed with IgA, not preventing IgA nephropathy. Furthermore, it is noted that in this example the only route of administration for the TACI-Fc fusion protein is subcutaneous injection, and there is no evidence that any other route of administration is acceptable for appropriate delivery/function of the fusion protein. Furthermore, it is noted that the instant specification provides no specific guidance on/examples of TACI extracellular domain truncations that are functional outside of the truncation that corresponds to instant SEQ ID NO: 1 (see Paragraph 0009). Similarly, the instant specification provides no specific guidance on/examples of mutated immunoglobulin constant regions outside of the specific mutations of P3T, L8P, L14A, L15E, G17A, A110S, P111S, and A173T relative to instant reference SEQ ID NO: 2; it is specifically noted that instant SEQ ID NO: 3 is the exemplary immunoglobulin constant region which comprises all of the above-listed mutations (see Paragraphs 10-13).
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to use the instantly claimed methods to prevent IgA nephropathy with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
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.
(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.
Claim(s) 1-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Clinical Study ID NCT04291781 (Version 2, Available 03/02/2020; herein after referred to as "NCT") as evidenced by WO 2022/206872 A1 (machine translation of the description utilized; herein after referred to as “Langyong”).
NCT discloses a study of RC18 (i.e., Tai Ai) in the treatment of human subjects with IgA nephropathy (Study Identification and Study Description). It is specifically noted that that RC18 is the research name for Telitacicept, and Tai Ai (or Tai’ai) is the brand name of the drug in China. The study is an interventional treatment, Phase II randomized study (see Study Design) wherein the arms of the study include those depicted in the table below (Arms and Interventions); the study discloses administering RC18 to a patient at a dose of 160 mg or 240 mg subcutaneously once a week, continuously for 24 weeks, for the treatment of IgA nephropathy.
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It is particularly noted that RC18 in the study is indicated as being formulated for injection (Study Description); one of ordinary skill in the art would understand that RC18 formulated for injection comprises the fusion protein itself formulated with a pharmaceutically acceptable carrier suitable for injection. Thus, the ordinary practitioner would immediately envision the protein (which would be powder alone) is dissolved into solution and thus has a carrier for injection. It is further noted that the structure (i.e., sequence) corresponding to RC18/Telitacicept/Tai Ai is an inherent feature of the fusion protein, and said sequence is evidenced by Langyong; Langyong SEQ ID NO: 12 is identified as Telitacicept, which is a TACI-Fc fusion protein and is a 100% match to instantly claimed SEQ ID NO: 4.
According to MPEP 2112(II):
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed. Cir. 1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form of the compound because practicing the process in the prior art to manufacture the anhydrous compound "inherently results in at least trace amounts of" the claimed hemihydrate even if the prior art did not discuss or recognize the hemihydrate); In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. "The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.").
Thus, the sequence corresponding to RC18/Telitacicept/Tai Ai corresponds to full-length instant SEQ ID NO: 4, and the method disclosed by NCT therefore meets all of the structural/sequence limitations of instant claims 1-10 and 15, and further meets the dosages/administration schedule/route of instant claims 11-13, and as a result also meets the functional requirement of being able to bind Blys and/or APRIL. It is further noted that NCT discloses that all patients included in the study must have a biopsy confirmed diagnosis of IgA nephropathy, but patients having any secondary IgA nephropathy are excluded (Eligibility); thus, the study of NCT is specific to patients having primary IgA nephropathy.
As such, NCT anticipates instant claims 1-15 as evidenced by Langyong.
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 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-11 of copending Application No. 17/052,079 (herein after referred to as "reference application") in view of Clinical Study ID NCT04291781 (Version 2, Available 03/02/2020; herein after referred to as "NCT").
Reference application claim 1 is drawn to a method for treating systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical preparation of a recombinant TACI-Fc fusion protein in a dose of 80, 160 or 240 mg per administration, wherein the recombinant TACI-Fc fusion protein has the sequence as shown in SEQ ID NO: 1, and wherein the subject has moderate to severe SLE prior to receiving the pharmaceutical preparation. Claims 4-5 disclose administration schedules, comprising administration once every week, every two weeks, every three weeks, or every four weeks. Claims 6-7 disclose pharmaceutical preparations that are lyophilized or liquid preparations. Claim 9 discloses that the administration route is via subcutaneous administration. Claims 10-11 disclose that the pharmaceutical preparations are administered to the subject consecutively for 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, or more. Thus, the claims of the reference application read on the administration of TACI-Fc fusion proteins for the treatment of an autoimmune condition in subjects in need thereof, wherein the reference application further discloses pharmaceutical formulations, dosages, and dosing schedules. However, it is noted that the reference application does not teach/suggest administering a TACI-Fc fusion protein to a patient for the treatment IgA nephropathy, nor a TACI-Fc fusion protein that is Telitacicept. These deficiencies are remedied by NCT.
NCT discloses a study of RC18 (i.e., Tai Ai) in the treatment of human subjects with IgA nephropathy (Study Identification and Study Description). It is specifically noted that that RC18 is the research name for Telitacicept, and Tai Ai (or Tai’ai) is the brand name of the drug in China. The study is an interventional treatment, Phase II randomized study (see Study Design) wherein the arms of the study include those depicted in the table below (Arms and Interventions); the study discloses administering RC18 to a patient at a dose of 160 mg or 240 mg subcutaneously once a week, continuously for 24 weeks, for the treatment of IgA nephropathy.
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It is particularly noted that RC18 in the study is indicated as being formulated for injection (Study Description); one of ordinary skill in the art would understand that RC18 formulated for injection comprises the fusion protein itself formulated with a pharmaceutically acceptable carrier suitable for injection. It is further noted that the structure (i.e., sequence) corresponding to RC18/Telitacicept/Tai Ai is an inherent feature of the fusion protein, and said sequence is evidenced by Langyong; Langyong SEQ ID NO: 12 is identified as Telitacicept, which is a TACI-Fc fusion protein and is a 100% match to instantly claimed SEQ ID NO: 4.
According to MPEP 2112(II):
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed. Cir. 1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form of the compound because practicing the process in the prior art to manufacture the anhydrous compound "inherently results in at least trace amounts of" the claimed hemihydrate even if the prior art did not discuss or recognize the hemihydrate); In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. "The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.").
Thus, the sequence corresponding to RC18/Telitacicept/Tai Ai corresponds to full-length SEQ ID NO: 4, and the method disclosed by NCT therefore meets all of the structural/sequence limitations of instant claims 1-10 and 15, and further meets the dosages/administration schedule/route of instant claims 11-13, and as a result also meets the functional requirement of being able to bind Blys and/or APRIL. It is further noted that NCT discloses that all patients included in the study must have a biopsy confirmed diagnosis of IgA nephropathy, but patients having any secondary IgA nephropathy are excluded (Eligibility); thus, the study of NCT is specific to patients having primary IgA nephropathy.
The reference application and NCT are considered to be analogous to the present invention as they are in the same field of TACI-Fc fusion proteins and autoimmune conditions. Therefore, it would have been obvious to one of ordinary skill in the art that the method of treatment disclosed by the reference application could be applied to patients with IgA nephropathy (including primary IgA nephropathy) as disclosed by NCT, because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to apply the method of the reference application (i.e., administering a TACI-Fc fusion protein/pharmaceutical formulation) in cases of IgA nephropathy as a therapeutic intervention because the prior art (i.e., NCT) discloses using Telitacicept/RC18/Tai Ai in such cases; furthermore both conditions are autoimmune conditions and as such a therapeutic effect in either condition would be reasonably expected.
This is a provisional nonstatutory double patenting rejection.
Similarly, claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the copending Application Nos. listed below in view of Clinical Study ID NCT04291781 (Version 2, Available 03/02/2020; herein after referred to as "NCT").
Application No.
Brief Description of the Invention
Pertinent Claims
17310431
Aqueous Liquid Pharmaceutical Formulation of TACI-Fc Fusion Protein and Method of Treating an Autoimmune Disease Thereof
1, 18
18257872
Method for Treating Sjogren's Syndrome Comprising Administering TACI-Fc Fusion Protein
1-9, 12-17
18705927
Method for Treating Myasthenia Gravis Comprising Administering TACI-Fc Fusion Protein and Medicament Thereof
1-9, 11-13, 18, 20
18730789
Liquid Formulation of TACI-Fc Fusion Protein, Method of Production, Pharmaceutical Product, Pre-Filled Syringe, and Method of Treating an Autoimmune Disease Thereof
1, 11-12, 17-19, 24
19114798
Method for Treating Membranous Nephropathy Comprising Administering TACI-Fc Fusion Protein
1-9, 15-18
The above-listed reference applications at a minimum read on (i) TACI-Fc fusion proteins, (ii) pharmaceutical formulations thereof, and/or (iii) methods for the treatment of autoimmune diseases comprising administering said TACI-Fc fusion proteins. However, it is noted that not all of the above-listed reference applications necessarily read on (i) Telitacicept as a TACI-Fc fusion protein, (ii) dosages/dosing schedules of TACI-Fc fusion proteins, and/or (iii) the treatment of IgA nephropathy. These deficiencies are remedied by NCT.
NCT discloses a study of RC18 (i.e., Tai Ai) in the treatment of human subjects with IgA nephropathy (Study Identification and Study Description). It is specifically noted that that RC18 is the research name for Telitacicept, and Tai Ai (or Tai’ai) is the brand name of the drug in China. The study is an interventional treatment, Phase II randomized study (see Study Design) wherein the arms of the study include those