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
The amended claim set filed 06/30/2023 is entered. Claims 1-17 are currently pending and under consideration. Claim 17 is amended.
Priority
The instant application is a 371 of PCT/KR2021/008000 (filed 06/25/2021). The effective filing date of instant claims 1-17 is 06/25/2021.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted 03/13/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, each information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosure
ST.25 REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
The Incorporation by Reference statement in the Specification entered 06/30/2023 refers to a File Name (MUNO-009/01US_SeqList_ST25) that does not match the file name of current working copy of the Sequence Listing version number 2.1 entered 06/30/2023 (18012600_2_1). The file name of the sequence listing must match the file name of sequence listing reported in the Incorporation by Reference statement in the Specification.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings filed on 12/22/2022 are objected to under 37 CFR 1.83(a) because they fail to show, as described in the specifications, the lines and bars in the plots clearly distinguishable. For example, in Figure 2, the lines for each pH condition are indistinguishable. For example, in Figure 4, it is unclear which bar corresponds to which condition. The examiner has not made an exhaustive list of all the figures for which these objections apply. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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.
In addition to Replacement Sheets containing the corrected drawing figure(s), applicant is required to submit a marked-up copy of each Replacement Sheet including annotations indicating the changes made to the previous version. The marked-up copy must be clearly labeled as “Annotated Sheets” and must be presented in the amendment or remarks section that explains the change(s) to the drawings. See 37 CFR 1.121(d)(1). Failure to timely submit the proposed drawing and marked-up copy will result in the abandonment of the application.
Specification
The amended specification filed 06/30/2023 is acknowledged and entered.
The disclosure is objected to because of the following informalities: Tables 25, 29-30, and 34-35 are illegible. None of the formulation conditions in the table can be examined.
Appropriate correction is required.
The use of the term AMICON (e.g. Specification, page 14, Table 4), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
A legible substitute specification in compliance with 37 CFR 1.52(a) and (b) and 1.125 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 6, 14-16 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “less” in claim 6 and 14-16 is a relative term which renders the claim indefinite. The term “less” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The applicant is advised to amend the claims to recite a closed range.
The term “increased” in claims 14-16 is a relative term which renders the claim indefinite. The term “increased” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what the reference point of stability is. Furthermore, the pharmaceutical formulation itself has many components that could be assigned a different measurement standard and reference point of stability.
The use of parenthesis in claims 14-16 further render the claims indefinite. The applicant is advised to amend the claims to explicitly state the storage conditions without relative terms and parenthesis.
Claims 14-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as it contains a lab designation HL161BKN for an antibody. The applicant must define the antibody by the specific SEQ ID NO. for its variable heavy chain CDR1-3 and variable light chain CDR1-3 and/or the SEQ ID NO. for its variable heavy chain and variable light chain.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 17 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-10 and 12-17 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 claims are drawn to a pharmaceutical formulation having a pH of 4.0 to 8.0, comprising (a) an anti-FcRn antibody or a fragment thereof, (b) at least one additive selected from mannitol, sorbitol, arginine, histidine, glycine and salts thereof, (c) a buffer system selected from citrate or histidine, and (d) a surfactant.
Dependent claims 2-10 and 12-17 add the following limitations to the formulation of claim 1: wherein the additive is arginine or a salt thereof (instant claim 2), and the buffer system is histidine (instant claim 3); wherein the surfactant is polysorbate (instant claim 4); wherein the formulation further comprises of methionine (instant claim 5); wherein the pharmaceutical formulation is in the form of an injection (instant claim 6); wherein the pharmaceutical formulation has a viscosity of 20 cP or less (instant claim 7); wherein the pharmaceutical formulation has an osmolality of 250 mOs/kg to 500 mOs/kg (instant claim 8); wherein the concentration of the anti-FcRn antibody or fragment thereof is 50 mg/mL to 250 mg/mL (instant claim 9); wherein the concentration of the anti-FcRn antibody or fragment thereof is 80 mg/mL to 250 mg/mL; wherein the pH of the pharmaceutical formulation is 4.0 to 7.0 (instant claim 10); wherein the pharmaceutical formulation is administered subcutaneously (instant claim 12); wherein the pharmaceutical formulation comprises (a) 50 mg/mL to 250 mg/mL of an anti-FcRn antibody,(b) 50 to 250 mM L-arginine or a hydrochloride salt thereof, (c) 50 to 250 mM L-histidine buffer, and (d) 0.01 to 0.05% polysorbate 20, and the pharmaceutical formulation has a pH of 4.0 to 7.0 (instant claim 13); wherein the pharmaceutical formulation has increased stability, wherein the amount of aggregates and fragments of HL161BKN is 10% or less when stored for 6 months under an accelerated condition (instant claim 14); wherein the pharmaceutical formulation has increased stability, wherein the amount of aggregates and fragments of HL161BKN is 10% or less when stored for 36 months under a long-term storage condition (5°C) (instant claim 15); wherein the amount of aggregates and fragments of HL161BKN is 5.0% or less when stored for 36 months under a long-term storage condition (5°C) (instant claim 16); wherein the pharmaceutical formulation is for the treatment of an autoimmune disease selected from the group consisting of myasthenia gravis, thyroid eye disease, warm autoimmune hemolytic anemia, neuromyelitis optica, immune thrombocytopenic purpura, pemphigus vulgaris, chronic inflammatory demyelinating polyneuropathy, lupus nephritis, and membranous nephropathy (instant claim 17).
Regarding claims 1-10 and 12-17, the specification teaches a formulation optimized for HL161BKN, which is an anti-FcRn antibody. The specification teaches the trial formulations and measured properties of these formulations to arrive at the optimized formulation for HL161BKN (Figures 2-20). Stability of the formulation was measured based on the formation of aggregation and fragments (Figures 4-5, 7, 9-19) when stored at conditions outlined in Tables 5-11, 28, and 33.
Regarding claim 13, the specification teaches screening trial formulations and formulation stability results comprising of histidine concentrations in the range of 50-150 mM (Table 11, Figure 17-18).
Regarding claim 17, the specification teaches that a therapeutic agent for autoimmune disease using an FcRn antibody is being studied (Korean Patent Publication No. 10-2014-0147606). The specification further teaches this antibody blocks FcRn (Neonatal Fc Receptor), which is involved in the recycling of IgG, and increases the catabolism of IgG in the body, thereby lowering the levels of autoantibodies to treat the diseases. The specification also teaches that, in order to apply this antibody to severe autoimmune diseases such as pemphigus vulgaris, neuromyelitis optica, and myasthenia gravis, which are caused by the generation of an autoantibody against an autoantigen in the body, a formulation optimized for this antibody and a formulation optimized for the administration method are required (Background Art, paragraphs 3-4)
The formulation, wherein the anti-FcRn antibody is the antibody comprising of the sequences disclosed in claim 11, meets the written description provision of 35 U.S.C. 112, first paragraph.
The formulation, wherein the histidine concentration is within 50-150 mM of instant claim 13 meets the written description provision of 35 U.S.C. 112, first paragraph.
However, claims 1-10 and 12-17 encompass more than just the HL161BKN antibody taught in the specification and the antibody taught in claim 11. The claims broadly encompass the entire genus of anti-FcRn antibodies and a fragment thereof, which could include any class, subclass, or fragment variant of antibodies.
The specification teaches that this formulation was optimized to work for the one species of antibody which is an IgG1 antibody; however, this is not deemed to be predictive of the stability of all anti-FcRn antibodies and fragment thereof that have different structures and therefore interact differently with the components of the formulation. The physiochemical stability of antibodies in solution is linked, in part, to their protein structure (Basle, Y. et al; Published 2020; Physicochemical Stability of Monoclonal Antibodies: A Review; Journal of Pharmaceutical Sciences (109) pages 169-190; see Abstract). Furthermore, Zhang et al teaches that there are no methods for predicting the overall propensity of antibodies to interact non-specifically with various types of molecules or themselves based simply on their primary structures and their corresponding sequence-based solvent accessibilities” (Zhang, Y., et al; Published 2021; Physicochemical rules for identifying monoclonal antibodies with drug-like specificity; Mol Pharm. 17 (7) pages 2555-2569; see section Discussion, paragraph 1). Anti-FcRn antibodies span a wide range of antibodies, such as but not limited to, IgG2a (e.g. clone 2B3B11), which for example, have a different number of inter-heavy chain disulfide bonds than IgG1 antibodies (Vidarsson, G., et al., Published 2014; IgG Subclasses and Allotypes: From Structure to Effector Functions; Front Immunol 5(20), see Table 1); and IgG4 antibodies (Zhu, L., et al; Published 2023; FcRn inhibitors: a novel option for the treatment of myasthenia gravis; Neural Regen Res. 18(8); pages 1637-1644; see Table 1), which is a subclass that have higher chemical stability than IgG1 (Neergaard, M., et al; published 2014; Stability of Monoclonal Antibodies at High-Concentration: Head-to-Head Comparison of the IgG1 and IgG4 Subclass; Jour of Pharm Sci 103(1) page 115-127; see Abstract). Neergaard teaches that an IgG1 molecule with the same variable region as an IgG4 molecule still had a lower chemical stability than the IgG4 molecule. IgG1 molecules have also been shown to be more stable than IgG2 molecules in formulations by differential scanning calorimetry (Alekseychyk, L., et al; Published 2014; High-Throughput Screening and Stability Optimization of Anti-Streptavidin IgG1 and IgG2 Formulations; SLAS Discovery 19(9) pages 1290-1301; see, for example, section Thermostability Screening by DSF, paragraph 1), which is the same method of measuring thermodynamic stability as in the instant application.
Furthermore, although the disclosure recites one species of anti-FcRn antibody, which is the HL161BKN antibody comprising of the CDR sequences disclosed in SEQ ID NO. 5-10, disclosure of this one species is not enough to show possession of the entire class of anti-FcRn antibodies. Furthermore, the set of six CDRs disclosed are specific to the FcRn antagonism of this one disclosed anti-FcRn antibody, but not to all anti-FcRn antibodies. The disclosure does not teach any common features that predict FcRn antagonism in anti-FcRn antibodies or fragments thereof that would allow one skilled in the art to produce other species of anti-FcRn antibodies or fragments thereof. Therefore, one skilled in the art cannot reasonably envision this formulation being optimal for stabilizing all anti-FcRn antibodies and fragments thereof in the instant claims.
Furthermore, Figure 1 of the instant application teaches, for example, that the CH2 domain, which is within the Fc region of an antibody, of the HL161BKN antibody has a lower Tm value than the Tm of the Fab region of the HL161BKN antibody. Therefore, one skilled in the art cannot reasonably envision this formulation being optimal for stabilizing all anti-FcRn antibodies and fragments thereof in the instant claims if fragments of the antibody that has been reduced to practice in the instant application already exhibit different starting Tm, which is used in the application as one indicator of thermodynamic stability.
Finally, Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Regarding claim 13, the claims broadly encompass a range of histidine concentrations between 50-250 mM. The specification teaches the effects of histidine concentration in the range 50-150 mM. However, this histidine concentration range is not deemed to be predictive of the effects of histidine at all concentrations, specifically at higher concentrations than 150 mM, as is claimed in instant claim 13. Lv et al teaches that although histidine can provide stabilizing benefits to antibody concentration at some concentrations, an increase from a stabilizing concentration of histidine can produce negative effects on the stability of antibody formulations (Lv, J., et al.; Published 2024; Histidine as a versatile excipient in the protein-based biopharmaceutical formulations; International Journals of Pharmaceutics 662(124472); see section “Histidine as an antioxidant and the opposite effect”, Paragraph 2).
Regarding claim 17, the claims broadly encompass the intended use of the anti-FcRn antibody or fragment thereof for the treatment of autoimmune disease. Although the intended use does not further limit the structure of the formulation, it raises the question of what the fragment thereof of the anti-FcRn is. The specification does not provide specific data showing the use of the formulation comprising of the antibody or a fragment thereof in the treatment of an autoimmune disease, although the specification teaches that the class of anti-FcRn antibodies, theoretically show potential in treating autoimmune disease based on their potential mechanism of action in recycling autoantibodies implicated in autoimmune diseases.
The disclosure does not define nor describe a fragment of an anti-FcRn antibody. A fragment of an anti-FcRn antibody could be any part of the antibody, such as fragments outside of the antigen-binding fragments or a single amino acid. Therefore, all fragment variants in the instant claim could not be capable of treating autoimmune diseases as claimed in Claim 17. Furthermore, de Haard et al teaches an FcRn antagonist, made from the Fc region of a human IgG modified to have a higher binding affinity to the FcRn receptor, for the treatment of the autoimmune disease immune thrombocytopenia (de Haard, H., Patent no. US12202900B2; Patent effective filing date: 06/07/2019; Compositions and methods for treating immune thrombocytopenia; see Definitions, paragraph 9). One skilled in the art would not normally consider the Fc region of an antibody for targeted therapy, as it is a commonly shared region of between classes of antibodies, and not normally target-specific. The FcRn receptor provides a unique case because this receptor binds to the Fc portion of antibodies. Therefore, in the instant application, a fragment of the anti-FcRn antibody used to treat an autoimmune disease cannot be understood to be the same set of antibody-binding fragments that one skilled in the art would normally understand as an antibody fragment. What types of fragments do the instant claims encompass and are they expected to behave the same way in the formulation as the full-length antibody that was reduced to practice in the specification?
The state of the art regarding antibody formulation is discussed by Basle et al. Basle et al teaches that optimal antibody formulations are specific to the antibody. However, there are some common features that formulations share, but formulation for one antibody is not predictive of other antibodies, especially with dissimilar protein structures.
The reference demonstrates the variability in the physiochemical stability of antibodies. Accordingly, one of skill in the art would conclude that the claimed invention encompasses a broad genus of anti-FcRn antibodies and fragment thereof that may not be stabilized by the formulation claimed. It should be noted that the specification has reduced to practice only one species of anti-FcRn antibody. Based on the teaching of the instant specification and the references, one of skill in the art would not conclude that the applicant was in possession of the claimed genus of anti-FcRn antibodies and fragment thereof.
The state of the art regarding histidine in antibody formulations is discussed by Lv et al, for example. Lv et al teaches that high concentrations of histidine can produce negative effects on the stability of antibody formulations (see section “Histidine as an antioxidant and the opposite effect”, Paragraph 2). The reference demonstrates the stabilizing effects of histidine but that increasing histidine concentration from a stabilizing concentration can have counter effects. Therefore, one skill in the art would not conclude that applicant was in possession of the formulations comprising of the range of histidine concentration claimed in claim 13 unless it was explicitly shown in the specification that these concentrations were reduced to practice and had the intended effect on the pharmaceutical formulation.
Consequently, the formulation comprising of an anti-FcRn antibody and fragment thereof and histidine concentration between 151-250 mM does not meet the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The applicant has not disclosed any species representative of the genus, which is highly variant. The applicant has not shown evidence of the trials using the full histidine concentration claimed. Applicant is reminded that Vas- Cath makes clear that the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6, 8-12, 14-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morichika et al (High concentration antibody-containing liquid formulation; Patent No. US11008394B2; filing date: 04/22/2019; hereafter referred to as Morichika) in view of Kim et al (FcRn Antibody-binding for FcRn for Treating Autoimmune Diseases; Patent App No. KR20180093128A; publication date: 03/08/2019; hereafter referred to as Kim).
Morichika teaches a pharmaceutical formulation comprising of an antibody (e.g. see Abstract, Paragraph 63) or an antibody fragment (e.g. see Paragraph 46); within a range of pH (Claim 11); additives with a list of additives comprising of arginine, histidine, and glycine (Paragraph 56); a buffer (paragraph 65) with a list of potential buffers that comprise of citrate or histidine (Paragraph 56); and a surfactant (Paragraph 66), meeting limitations in instant claim 1-17.
Morichika also teaches an antibody-containing formulation, wherein the additive is arginine and the buffer system is histidine (Paragraph 10-11), polysorbate as a preferred surfactant in the formulation (Paragraph 60), a formulation that further comprises methionine (Paragraph 64), and a formulation that falls within a range of pH (Claim 11), meeting limitations in instant claim 2-4 and 10.
Morichika also teaches the formulation prepared in the form of an injection, particularly suitable for subcutaneous injection (Paragraph 78), meeting limitations in instant claims 5 and 12.
Morichika also teaches an antibody-containing formulation and recites a formulation viscosity range (Paragraph 80), concentration range of the antibody (Paragraph 13), and the percentage of decomposition product of the antibody present over time at specific timepoint and temperature conditions (Paragraph 57), that falls within the ranges provided by limitations in instant claims 6, 8-9, and 14-16.
However, Morichika does not explicitly teach the antibody to specifically be an anti-FcRn antibody or fragment thereof, as in instant claims 1-17 and does not explicitly teach the specific anti-FcRn antibody, comprising of the heavy chain variable region and light chain variable region comprising the CDR regions, defined by their amino acid sequences, as recited in instant claim 11.
Regarding instant claims 1-17, Kim teaches a formulation composition comprising of an anti-FcRn antibody (Abstract) or fragment thereof (Paragraphs 42-43), specifically an anti-IL6 antibody of the IgG1 subclass. Kim teaches the addition of conventional pharmaceutically acceptable carriers, excipients, and additives (Paragraph 87), a buffer (Paragraph 87), a surfactant (Paragraph 87), and a formulation with a pH of 6.0 or 7.4 (Paragraph 117). Kim teaches the formulation composition comprising the anti-FcRn antibody as a formulation for injection (Paragraph 87).
Regarding instant claim 11, Kim teaches a pharmaceutical formulation wherein the anti-FcRn antibody comprises the disclosed amino acid sequences for the variable heavy and light chain CDR1-3 (Paragraph 60 and claim 4), which are the same sequences for the variable heavy and light chain CDR1-3 disclosed in instant claim 11. The sequence for heavy chain CDR1 is SEQ ID NO. 5 in the instant application has 100% homology to SEQ ID NO. 27 in Kim. The sequence for heavy chain CDR2 is SEQ ID NO. 6 in the instant application has 100% homology to SEQ ID NO. 28 in Kim. The sequence for heavy chain CDR3 is SEQ ID NO. 7 in the instant application has 100% homology to SEQ ID NO. 29 in Kim. The sequence for light chain CDR1 is SEQ ID NO. 8 in the instant application has 100% homology to SEQ ID NO. 30 in Kim. The sequence for light chain CDR2 is SEQ ID NO. 9 in the instant application has 100% homology to SEQ ID NO. 31 in Kim. The sequence for light chain CDR3 is SEQ ID NO. 10 in the instant application has 100% homology to SEQ ID NO. 32 in Kim.
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to try the finite number of formulation conditions taught in Morichika optimized using an IgG1 antibody with the anti-FcRn IgG antibody from Kim, which is the antibody reduced to practice in the claimed invention and is another IgG1 antibody, thereby arriving at the claimed invention.
Morichika teaches a formulation suitable for antibodies and fragments thereof, that helps enable stable, high antibody concentration for use in, for example, injectable antibody formulations, suitable for, as an example, subcutaneous injection (Paragraph 87). The formulation was specifically formulated for a humanized anti-IL6 antibody of the IgG1 subclass (Paragraph 49). There is a recognized need in the biopharmaceutical field to create formulations appropriate for maintain the integrity of antibodies. One skilled in the art would recognize the teachings of Morichika as candidate formulations from a finite number of identified, predictable potential solutions as it taught a formulation optimized for an IgG1 subclass, of which the antibody from Kim also belongs to.
A person of ordinary skill in the art would have been motivated to formulate an anti-FcRn antibody and the specific anti-FcRn antibody taught in Kim according to the formulations teachings of Morichika because these antibodies have therapeutic potential, but only if they can be suitably formulated for pharmaceutical administration. The formulations taught in Morichika is optimized for stable high-concentration antibody-containing liquid formulations, which is the foundation for developing injectable antibody-based therapeutics. Therefore, the substitution is also desirable.
The person of ordinary skill in the art would have had a reasonable expectation of success because Morichika teaches this formulation is developed for antibodies. The specific example in Morichika is an IgG1 antibody, which is the same antibody subclass as the specific example of antibody taught in Kim and in the instant application. Because antibodies of the same subclass share structural homology, and the components in the formulation work based on their interaction with these protein structures, one skilled in the art would expect that antibodies in the same subclass would have similar physiochemical stability in the same formulation or that it would be obvious to try to substitute one antibody in the same subclass for another in a formulation .
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385 (2007), discloses that choosing from a finite number of identified, predictable solutions, with reasonable expectation of success is obvious. In the instant application, the formulations of Morichika provides a finite set of conditions that could provide a solution to the antibody taught by Kim, where both the IgG in Morichika and the IgG in Kim belong to the IgG1 subclass and thus sharing high structural homology. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claims 7 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Morichika in view of Kim as applied to claims 1-6, 8-12, 14-17 above, and further in view of Chen et al (Influence of histidine on the stability and physical properties of a fully human antibody in aqueous and solid forms; Pharm Res 20, 1952-1960; published 12/2003, hereafter referred to as Chen).
The teachings of Morichika and Kim are as described above.
Morichika also teaches the formulation compositions (see e.g. Table 1-1) comprising a concentration range of an anti-FcRn antibody (Claim 4), a concentration range of L-arginine or a hydrochloride salt thereof (Claim 12), and a concentration range of polysorbate 20 as a surfactant (Paragraph 60-61), that falls within the ranges provided by limitations of instant claim 13.
However, Morichika and Kim also does not explicitly teach the concentration of histidine buffer to be 50 to 250 mM L-histidine buffer, as in instant claim 13. The histidine concentration in these references are lower than the histidine concentration in instant claim 13.
Morichika and Kim also does not explicitly teach the osmolarity range of the formulation, as in instant claim 7.
Regarding claim 13, Chen teaches a histidine concentration optimized for an antibody formulation and minimal antibody aggregate formation was observed at approximately 60 mM. histidine (see page 1958, section Something to Be Aware of About Histidine Formulations, paragraph 1), which falls within the histidine concentration range of instant claim 13.
Regarding claim 7, since osmolality is based on the solutes in a fluid, it can be calculated based on the concentration of solutes in a formulation. The osmolality range provided in the instant claim is measured from the formulation variants disclosed in the instant application. The calculated osmolality of a formulation with the same solutes within the same concentration ranges disclosed in the instant application will yield the same calculated osmolality as disclosed in the instant application. Therefore, the formulation as taught by Morichika in view of Kim and further in view of Chen, which teaches all the limitations of the instant application will yield an osmolality within the osmolality range of the instant application.
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to improve the antibody-containing pharmaceutical formulations taught by Morichika and Kim by increasing the histidine concentration in the formulation to improve the stability of the antibody as taught by Chen, thereby arriving at the claimed invention.
A person of ordinary skill in the art would have been motivated to improve the formulation taught by Morichika and Kim, which is optimized to maintain antibody stability, by increasing the histidine concentration because Chen teaches that this concentration improves the antibody’s stability and reduces the formulation’s viscosity (see page 1958 and Figure 5), which is sought after for high-concentration antibody formulations. Therefore, the improvement is also desirable for the formulating more stable antibody-containing pharmaceutical formulations.
The person of ordinary skill in the art would have had a reasonable expectation of success because Chen teaches that histidine concentration in bulk solution inhibits antibody aggregates upon storage and enhanced solution stability of the antibody, and that this histidine function is not specific to any one antibody, but rather works by disrupting charge-charge interactions in self-associations between antibody molecules (page 1958).
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385 (2007), discloses the use of a known technique to improve a similar product in the same way is considered obvious. In the instant application, the use of a higher histidine concentration in Chen is a known technique to improve on a similar antibody formulation with a lower histidine concentration that is also formulated to improve antibody stability, as taught by Morichika and Kim. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
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.
Conclusion
No claim is allowed.
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/B.C./Examiner, Art Unit 1645
November 26, 2025
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674