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
Applicant’s preliminary amendments and remarks, filed 12/30/2022, are acknowledged.
Claims 32-44 are canceled.
Claims 1, 3-12, 14-26, 28, and 30-31 are amended.
Claims 45-49 are new.
Claims 1-31 and 45-49 are pending.
DETAILED ACTION
Election/Restrictions
Applicant's group election with traverse of Group I, claims 1-31 and 45-46, in the reply filed on 02/05/2026 is acknowledged. The traversal is on the ground(s) that the Office has not established that there would be a serious burden to search and examine all the claims together. This is not found persuasive because the Applicant is arguing elements of a restriction under US practice, and not Unity of Invention restriction practice. Under US restriction practice, a product and a process of using the product can be shown to be distinct inventions if either or both of the following can be shown: (A) the process of using as claimed can be practiced with another materially different product; or (B) the product as claimed can be used in a materially different process. However, the instant case has been filed as a national stage entry of a PCT international application. As shown in Example 1 in Chapter 10.21 of the PCT International Search and Preliminary Examination Guidelines (which can be found at https://www.wipo.int/pct/en/texts/ispe/10_21_36.html ), claims in different categories of inventions are permitted, but unity of invention is lacking if the technical feature shared by all of the claims is known in the art. The Examiner provided Panousis et al (WO2013/014092 A1; publication date: 01/31/2013), Ma et al (US 8,613,919 B1; patent date: 12/24/2013), and ECA – Academy (https://www.gmp-compliance.org/gmp-news/what-are-the-regulatory-definitions-for-ambient-room-temperature-and-cold-chain ; publication date: 03/02/2017) in the restriction mailed on 11/05/2025, which demonstrates that the technical feature linking the inventions of Groups I and II does not constitute a special technical feature as defined by PCT Rule 13.2, as it does not define a contribution over the art. Therefore, Applicant’s argument regarding search burden is not considered under PCT 371. The requirement is still deemed proper and is therefore made FINAL.
Claims 47-49 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 02/05/2026.
Applicant’s species election without traverse of:
SEQ ID NO: 5 for the VH sequence;
SEQ ID NO: 6 for the VL sequence;
SEQ ID Nos: 7, 16, and 9 for the VH CDRs; and,
SEQ ID Nos: 12, 13, and 14 for the VL CDRs
in the reply filed on 02/05/2026 is acknowledged.
As such, claims 1-31 and 45-46 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/30/2022 and 10/28/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification (e.g., see pages 52 and 54) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The disclosure is objected to because of the following informalities:
Page 97: “Example 6: Stability of high concentration formulations n pre-filled syringes” should read “Example 6: Stability of high concentration formulations in pre-filled syringes”.
Appropriate correction is required.
The use of the term Triton, Pluronic, Dionex, UltiMate, and Unchained Labs, 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.
Claim Objections
Claims 1, 9, 10, 14, 15, 22, 30, and 31 are objected to because of the following informalities:
Claims 1, 9-10, 14-15, and 30-31: “stabiliser” and “stabilisers” should read “stabilizer” and “stabilizers”, respectively.
Claims 14-15 and 30-31: semi-colons should be used when listing components of the invention. For example, claim 14 should read “The formulation according to claim 1, wherein the formulation comprises 100 mg/ml to 110 mg/ml of the protein; a histidine buffer; and, polysorbate 80, proline, and arginine monohydrochloride as stabilizers, wherein the formulation has a pH of 5.5 to 6.5 and a viscosity of less than 10 mPa*s at 20°C”.
Claim 22: “antagonises” should read “antagonizes”.
Appropriate correction is required.
Claim Interpretation
Examiner acknowledges that Applicant defines “binds” in reference to the interaction of an antibody or an antigen binding fragment thereof with an antigen means that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the antigen (see page 39, lines 7-9).
Additionally, Examiner acknowledges that Applicant defines the term “specifically binds” or “binds specifically” to mean that an antibody or antigen binding fragment thereof reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular antigen or cell expressing same than it does with alternative antigens or cells (see page 39, lines 15-18).
Lastly, Examiner acknowledges that Applicant defines an activated form of Factor XII (FXIIa) includes the FXIIa alpha and FXIIa beta cleavage fragments (see page 40, lines 23 and 24)
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-31 and 45-46 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.
Claims 1 and 22 recites “binds to or specifically binds to” which renders the claims indefinite because while Applicant defines the term “specifically binds” or “binds specifically” to mean that an antibody or antigen binding fragment thereof reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular antigen or cell expressing same than it does with alternative antigens or cells (see page 39, lines 15-18), it is unclear what is considered “more frequently”, “more rapidly”, “greater duration”, and/or “greater affinity” without a standard to compare. As such, claims 1, 22, and their dependent claims are rejected because one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 14-15 and 30-31 recites “proline and arginine monohydrochloride”. It is unclear whether the monohydrochloride also applies to the proline.
Claim 22 recites “antagonizes activity of the Factor XII and/or an activated form thereof and/or antagonizes activation of the Factor XII and/or an activated form thereof”. The conjugation “and” renders the claim indefinite because it requires that the alternative conditions be present in same embodiment (e.g., antagonizing activity and antagonizes activation).
Claims 25-27 and 30-31 recite “set forth in SEQ ID NO: XX”. This language is indefinite because it is unclear if the amino acid is limited to the full sequence of the SEQ ID NO, or the amino acid sequence can be of any length as long as the SEQ ID NO is within the sequence, respectively. The term “set forth in SEQ ID NO: XX” could refer to any two amino acids joined by a peptide bond that appears within the sequence of SEQ ID NO:XX. As such, 25-27, 30, 31, and their dependent claims, are rejected.
Claims 30-31 recite “100 mg/ml and 170 mg/ml” renders the claim indefinite because the conjugation “and” requires that the alternative conditions be present in same embodiment.
Claim Rejections - 35 USC § 112(a) Written Description
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 1-31 and 45-46 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a liquid pharmaceutical formulation comprising at least 100 mg/ml of a protein comprising an antigen binding domain that binds to or specifically binds to Factor XII and/or an activated form thereof, an organic acid buffer, a non- ionic surfactant and an amino acid stabilizer, wherein the formulation has a pH of 5.0 to 6.5 and a viscosity of less than 30 mPa*s at 20 0C.
Claim 2 is drawn to the formulation according to claim 1, wherein the protein is present in the formulation at a concentration of at least 150 mg/ml.
Claim 3 is drawn to the formulation according to claim 1, wherein the protein is present in the formulation at a concentration of 160 mg/ml to 180 mg/ml.
Claim 4 is drawn to the formulation according to claim 1, wherein the formulation is an aqueous formulation
Claim 5 is drawn to the formulation according to claim 1, wherein the organic acid buffer is selected from the group consisting of a histidine buffer and a glutamate buffer.
Claim 6 is drawn to the formulation according to claim 1, wherein the organic acid buffer is a histidine buffer.
Claim 7 is drawn to the formulation according to claim 1, wherein the non-ionic surfactant is selected from the group consisting of polysorbate 80, polysorbate 20, and poloxamer 188.
Claim 8 is drawn to the formulation according to claim 1, wherein the non-ionic surfactant is polysorbate 80.
Claim 9 is drawn to the formulation according to claim 1, wherein the amino acid stabilizer is selected from the group consisting of proline, arginine, salts thereof, and a combination thereof.
Claim 10 is drawn to the formulation according to claim 1, wherein the amino acid stabilizer is proline.
Claim 11 is drawn to the formulation according to claim 1, wherein the formulation further comprises a polyol.
Claim 12 is drawn to the formulation according to claim 1, wherein the formulation comprises a histidine buffer, proline, and polysorbate 80.
Claim 13 is drawn to the formulation according to claim 12, wherein the formulation further comprises arginine monohydrochloride.
Claim 14 is drawn to the formulation according to claim 1, wherein the formulation comprises 100 mg/ml to 110 mg/ml of the protein, a histidine buffer, polysorbate 80 and proline and arginine monohydrochloride as stabilizers, wherein the formulation has a pH of 5.5 to 6.5 and a viscosity of less than 10 mPa*s at 20 °C.
Claim 15 is drawn to the formulation according to claim 1, wherein the formulation comprises 160 mg/ml to 180 mg/ml of the protein, a histidine buffer, polysorbate 80 and proline and arginine monohydrochloride as stabilizers, wherein the formulation has a pH of 5.5 to 6.5 and a viscosity of less than 10 mPa*s at 20 °C.
Claim 16 is drawn to the formulation according to claim 1, wherein the formulation has a pH of 5.8 to 6.4 and comprises 12 mM to 25 mM L-histidine buffer, 0.01 % to 0.03 % (w/v) polysorbate 80, 90 mM to 150 mM L- prolines and 100 mM to 160 mM L-arginine monohydrochloride.
Claim 17 is drawn to the formulation according to claim 1, wherein the formulation has a pH of 5.8 to 6.4 and comprises 20 mM L- histidine buffer, 0.02 % (w/v) polysorbate 80, 140 mM L-proline, and 150 mM L- arginine monohydrochloride.
Claim 18 is drawn to the formulation according to claim 1, wherein the viscosity of the formulation is less than 9 mPa*s at 20 °C
Claim 19 is drawn to the formulation according to claim 1, wherein the formulation has a density of 1.00 to 1.10 g/cm3 at 20 °C.
Claim 20 is drawn to the formulation according to claim 1, wherein the formulation comprises less than 10 % total aggregates of the protein.
Claim 21 is drawn to the formulation according to claim 1, wherein at least 90 % of the protein in the formulation is a monomer.
Claim 22 is drawn to the formulation according to claim 1, wherein the antigen binding domain binds to or specifically binds to Factor XII and/or an activated form thereof and antagonizes activity of the Factor XII and/or an activated form thereof and/or antagonizes activation of the Factor XII and/or an activated form thereof.
Claim 23 is drawn to the formulation according to claim 1, wherein the protein comprises an antigen binding domain of an antibody.
Claim 24 is drawn to the formulation according to claim 1, wherein the protein is selected from the group consisting of: (i) a single chain Fv fragment (scFv); (ii) a dimeric scFv (di-scFv); (iii) a diabody; (iv) a triabody; (v) a tetrabody; (vi) a Fab; (vii) a F(ab')2; (viii) a Fv; (ix) one of (i) to (viii) is linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) CH2 and/or CH3; or (x) an antibody.
Claim 25 is drawn to the formulation according to claim 1, wherein the protein comprises: (i) a VH comprising an amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 2 (ii) a VH comprising an amino acid sequence set forth in SEQ ID NO: 3 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 4; or (iii) a VH comprising an amino acid sequence set forth in SEQ ID NO: 5 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 6.
Claim 26 is drawn to the formulation according to claim 1, wherein the protein comprises: (i) a VH comprising: (a) a CDR1 comprising a sequence set forth in SEQ ID NO: 7; a CDR2 comprising a sequence set forth in SEQ ID NO: 8; and a CDR3 comprising a sequence set forth in SEQ ID NO: 9; or (b) a CDR1 comprising a sequence set forth in SEQ ID NO: 7; a CDR2 comprising a sequence set forth in SEQ ID NO: 10; and a CDR3 comprising a sequence set forth in SEQ ID NO: 11; or (c) a CDR1 comprising a sequence set forth in SEQ ID NO: 7; a CDR2 comprising a sequence set forth in SEQ ID NO: 10; and a CDR3 comprising a sequence set forth in SEQ ID NO: 9; or (d) a CDR1 comprising a sequence set forth in SEQ ID NO: 7; a CDR2 comprising a sequence set forth in SEQ ID NO: 16; and a CDR3 comprising a sequence set forth in SEQ ID NO: 9; and/or (ii) a VL comprising: (a) a CDR1 comprising a sequence set forth in SEQ ID NO: 12; a CDR2 comprising a sequence set forth in SEQ ID NO: 13; and a CDR3 comprising a sequence set forth in SEQ ID NO: 14; or (b) a CDR1 comprising a sequence set forth in SEQ ID NO: 12; a CDR2 comprising a sequence set forth in SEQ ID NO: 13; and a CDR3 comprising a sequence set forth in SEQ ID NO: 15.
Claim 27 is drawn to the formulation according to claim 26, wherein the protein comprises a VH comprising a CDR2 set forth in SEQ ID NO: 10 wherein the X at position 3 is D, the X at position 4 is I, the X at position 5 is P, the X at position 6 is T, the X at position 7 is K, and the X at position 8 is G.
Claim 28 is drawn to the formulation according to claim 1, wherein the protein comprises an IgG4 constant region.
Claim 29 is drawn to the formulation according to claim 28, wherein the IgG4 constant region is a stabilized IgG4 constant region.
Claim 30 is drawn to the formulation according to claim 1, wherein the formulation comprises 100 mg/ml and 170 mg/ml of the protein, a histidine buffer, polysorbate 80 and proline and arginine monohydrochloride as stabilizers, wherein the formulation has a pH of 5.5 to 6.5 and a viscosity of less than about 30 mPa*s at 20°C and wherein the protein comprises a VH comprising an amino acid sequence set forth in SEQ ID NO: 5 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 6.
Claim 31 is drawn to the formulation according to claim 1, wherein the formulation comprises 100 mg/ml and 170 mg/ml of the protein, a histidine buffer, polysorbate 80 and proline and arginine monohydrochloride as stabilizers, wherein the formulation has a pH of 5.5 to 6.5 and a viscosity of less than about 30 mPa*s at 20°C and wherein the protein comprises: (i) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 7; a CDR2 comprising a sequence set forth in SEQ ID NO: 16; and a CDR3 comprising a sequence set forth in SEQ ID NO: 9; and (ii) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 12; a CDR2 comprising a sequence set forth in SEQ ID NO: 13; and a CDR3 comprising a sequence set forth in SEQ ID NO: 14.
Claim 45 is drawn to a prefilled syringe comprising the formulation according to claim 1.
Claim 46 is drawn to an autoinjector device comprising the formulation according to claim 1.
The specification discloses of assessing formulation excipients using a monoclonal anti-Factor XII antibody (affinity matured 3F7 or 3F7aff) (see Example 1). In the case of buffer exchanges with 20 mM glutamate buffer at pH 5.5, it was observed that the antibody solution formulated at 100 mg/ml did not reach the pH target (measured pH was 5.65) even after extensive buffer exchanges (see page 69, lines 15-17). Twelve formulations were evaluated to assess the effect of four different excipients (phenylalanine, proline, arginine, and sorbitol) in three different buffers (glutamate, succinate, and histidine) at pH 5.5 on the stability of the antibody at concentration of 100 mg/ml (F11-F22, Table 2); additionally, a formulation containing glutamate and histidine at pH 5.5 was evaluated (F23) (see page 72, lines 10-14). The comparison of Tonset and Tm values showed comparable thermal stability for all formulations containing phenylalanine, proline and sorbitol; a similar stability was observed for formulation F23, containing histidine and glutamate (see page 72, lines 25-27). The specification discloses that concentrated samples (≥200 mg/ml) remained soluble and no negative effects on antibody stability were observed for all tested formulations (see page 75, lines 32 and 33).
The specification also discloses evaluating the protective effect of non-ionic surfactants (polysorbate 80, polysorbate 20, and poloxamer 188) on antibody soluble and insoluble aggregates formation in freeze-thaw and agitation studies (see page 77, lines 2-4). The suppression effect was similar for all tested surfactants; however, the reduction of particles observed for formulations containing PS-80 was the most beneficial (see page 78, lines 12 and 13). Also, the protective effect observed was slightly better for PS-80 concentration of 0.05% than for 0.02% (see page 78, lines 13-15).
The specification discloses of formulation FDOE12 comprising 100 mg/ml antibody, 20 mM Glutamate, 100 mM Arginine, 0.05% PS-80, pH 5.5 (see Example 2). Adding arginine showed a gradual decrease in ΔG with antibody concentration and after adding proline showed a significant reduction in aggregate formation (see pages 81 and 82). The models generated for histidine buffer ± proline showed an upward trend in the accumulation of charged variants as a function of pH; similar to glutamate buffer, the presence of proline in histidine buffer reduced the accumulation of charged variants at all tested pH levels (see page 84, lines 24-26).
Example 3 assesses the suitability of formulations F37 and F38 of the antibody for manufacture and clinical application in a liquid formulation at 100 mg/ml, wherein F37 comprises 100 mg/ml antibody, 100 mM glutamate at pH 5.6, 150 mM proline and 0.05% PS-80; and F38 comprises 100 mg/ml antibody, 20 mM histidine at pH 5.8, 150 mM proline, 80 mM sorbitol and 0.05% PS-80 (see page 85, lines 14-23). Example 4 discloses the preparation of higher-concentration formulation (about 200 mg/ml antibody). The high concentration antibody formulations exhibited long term thermal stability (see Table 7; Examples 5 and 6)
However, the specification fails to disclose that Applicant was in possession of the genus of liquid pharmaceutical formulations as claimed. Specifically, the specification fails to disclose that Applicant was in possession of the large genus of proteins, organic acid buffers, non-ionic surfactants, and amino acid stabilizers solely described by their function without providing the corresponding structure.
Although the specification discloses of several formulation excipients using a monoclonal anti-Factor XII antibody (affinity matured 3F7 or 3F7aff), the claims are not limited to these inhibitors, and are inclusive of any liquid pharmaceutical formulation comprising at least 100 mg/ml of any protein comprising an antigen binding domain that binds to or specifically binds to Factor XII and/or an activated form thereof, any organic acid buffer, any non-ionic surfactant and any amino acid stabilizer, wherein the formulation has a pH of 5.0 to 6.5 and a viscosity of less than 30 mPa*s at 20 0C. This indicates that there are hundreds, if not thousands, of possible liquid formulations encompassed by the claims. Thus, the claims encompass a vast genus of liquid formulations that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of liquid formulations because, inter alia, the specification does not disclose a correlation between the necessary structure of the inhibitor and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies and therapeutic agents claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of liquid formulations. The disclosure of only one or two 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.") (MPEP 2163).
The instant claims do not fully describe the structure of the proteins, organic acid buffers, non-ionic surfactants, and amino acid stabilizers within a liquid formulation to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of liquid formulations, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous liquid formulations had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of liquid formulations claimed only by a partial structure and functional characteristic(s). Thus the liquid formulations described by the instant claims encompasses an overly broad genus, the structure of the proteins, organic acid buffers, non-ionic surfactants, and amino acid stabilizers, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of proteins by the functions of binding to or specifically binding to Factor XII and/or an activated form thereof. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed liquid formulations, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, 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.
Regarding the encompassed proteins that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies and therapeutic agents that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies/therapeutic agents or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside 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 and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that 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. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed liquid formulations could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all liquid formulations.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed liquid formulations. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of liquid formulations as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 103
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 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.
Panousis and Ma
Claims 1, 4-9, 18, 20, 22-29, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Panousis et al (WO 2017/173494 A1; publication date: 10/12/2017) and further in view of Ma et al (US 8,613,919 B1; patent date: 12/24/2013) and ECA – Academy (https://www.gmp-compliance.org/gmp-news/what-are-the-regulatory-definitions-for-ambient-room-temperature-and-cold-chain ; publication date: 03/02/2017; previously submitted with the restriction mailed 11/05/2025).
With respect to the claimed protein within the liquid formulation, Panousis et al disclose of inhibitory anti-factor XII/XIIa antibodies and methods of their use (see Abstract; entire document). Panousis et al disclose of aqueous pharmaceutical compositions comprising the claimed antibodies or antigen-binding fragments thereof and other substances such as pH adjusting buffering solutions (see page 54, lines 18-31). Specifically, Panousis et al disclose of FXII inhibitor, gVR115, comprising SEQ ID Nos: 18 and 19 which share 100% identity with instant SEQ ID Nos: 5 and 6. Additionally, Panousis et al disclose that the antibodies within the pharmaceutical compositions comprise a full human IgG4/lambda constant region (see pages 8, 15, and 46). Panousis et al also disclose that the claimed antibodies have treated conditions such as atherosclerosis (see Abstract). Panousis et al disclose that the pharmaceutical composition can be packaged in syringe (see page 57 and 58).
Panousis et al fail to disclose of the specific pharmaceutical compositions as claimed comprising an organic acid buffer, a non-ionic surfactant, and an amino acid stabilizer, wherein the formulation has a pH of 5.0 to 6.5 and a viscosity of less than 30 mPa*s at 20C.
However, Ma et al disclose of high concentration, salt-free antibody and other protein formulations that are substantially isosmotic and of low viscosity (see Abstract). Specifically, Ma et al disclose of a liquid Tissue Factor Pathway Inhibitor (TFPI) monoclonal antibody which is formulated with histidine, Tween 80 (i.e., polysorbate 80), and arginine at a pH within 5.0 and 6.0 (see Table 1). Ma et al disclose that the optimum pH for the stability of the formulation is between pH 5 and pH 6 when IV, IM, and subcutaneous injection are considered (see Example 3). The concentration of the monoclonal antibody in formulation is 100 mg/ml (see Table 1 – PH5.5HCARG through PH5.5HCARGMET). Ma et al disclose that the liquid pharmaceutical compositions have a viscosity under 5 mPa-S at 22°C (see Table 2). While Ma et al does not disclose of the viscosity at 20°C, it is known in the art that ambient or room temperature with respect to pharmaceutical products is at a range of 15°C - 25°C (see ECA – Academy). Therefore, one would have a reasonable expectation that the viscosity of the pharmaceutical formulation of Ma et al will not significantly change at 20°C because both 22°C and 20°C are within ambient temperature range. With respect to instant claim 20, Ma et al disclose that the percent aggregation formation for these high concentration formulations were less than 10% (see Tables 4-7).
Therefore, one of skill in the art would be motivated to combine the teachings of Panousis et al and Ma et al because Panousis et al disclose of inhibitory anti-factor XII/XIIa antibodies that treated atherosclerosis wherein pharmaceutical compositions comprising the claimed antibodies or antigen-binding fragments thereof and other substances such as pH adjusting buffering solutions (see page 54, lines 18-31). While Panousis et al does not disclose of the specific pharmaceutical formulations, one would modify the invention of Panousis with the high concentration formulations of Ma et al because Ma indicates that their claimed formulation demonstrated enhanced stability, especially at pH between pH 5 and pH 6. Thus, one would have a reasonable expectation that formulating the anti-factor XII/XIIa antibodies of Panousis with the formulations disclosed by Ma et al would optimize the stability of the pharmaceutical composition at 20°C (see MPEP 2144.05(II)(A) and 2144.05(II)(B)).
Panousis and Demopulos
Claims 1-13, 18, 20-29, and 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Panousis et al (WO 2017/173494 A1; publication date: 10/12/2017) and further in view of Demopulos et al (US 2018/00153988 A1; publication date: 06/07/2018).
With respect to the claimed protein within the liquid formulation, Panousis et al disclose of inhibitory anti-factor XII/XIIa antibodies and methods of their use (see Abstract; entire document). Panousis et al disclose of aqueous pharmaceutical compositions comprising the claimed antibodies or antigen-binding fragments thereof and other substances such as pH adjusting buffering solutions (see page 54, lines 18-31). Specifically, Panousis et al disclose of FXII inhibitor, gVR115, comprising SEQ ID Nos: 18 and 19 which share 100% identity with instant SEQ ID Nos: 5 and 6. Additionally, Panousis et al disclose that the antibodies within the pharmaceutical compositions comprise a full human IgG4/lambda constant region (see pages 8, 15, and 46). Panousis et al also disclose that the claimed antibodies have treated conditions such as atherosclerosis (see Abstract). Panousis et al disclose that the pharmaceutical composition can be packaged in syringe (see page 57 and 58).
Panousis et al fail to disclose of the specific pharmaceutical compositions as claimed comprising an organic acid buffer, a non-ionic surfactant, and an amino acid stabilizer, wherein the formulation has a pH of 5.0 to 6.5 and a viscosity of less than 30 mPa*s at 20C.
However, Demopulos et al disclose of stable, high-concentration low-viscosity formulations of MASP-2 inhibitory antibodies, kits comprising the formulations and therapeutic methods using the formulations (see Abstract). Specifically, Demopulos et al disclose of aqueous solutions comprising a buffer system having a pH from about 5.0 to about 7.0, wherein “about” means within ± 10% (see [0067] and [0089]-[0095]). Demopulos et al disclose of a formulation wherein the antibody is at a concentration of 185 mg/ml, L-histidine 20 mM, L-Arginine HCL (monohydrochloride) 200 mM, and polysorbate 80 0.01% and the pH is about 5.9 (see [0154]-[0155] and Table 2). Further, the viscosity measurement is at about 25C (i.e., 20°C is within range) because ideally a viscosity below about 25 cP ensures a realistically syringeable subcutaneous therapeutic product (see [0224]-[0225]). Fig. 3 shows a formulation with proline/glutamate also produced a viscosity under 20 cP at a pH of 6.0 (see [0261]). Demopulos et al disclose that the formulation can further comprise a polyol (see [0351]). With respect to instant claims 20 and 21, Demopulos et al measure the aggregates of the formulation (HMW) wherein the percentage is less than 10% (see [0059] and Table 10) and the percentage of monomers was at least 90% (see Table 11). Lastly, Demopulos et al disclose that this formulation can be delivered in a pre-filled syringe or autoinjector (see [00004]).
Therefore, one of skill in the art would be motivated to combine the teachings of Panousis et al and Demopulos et al because Panousis et al disclose of inhibitory anti-factor XII/XIIa antibodies that treated atherosclerosis wherein pharmaceutical compositions comprising the claimed antibodies or antigen-binding fragments thereof and other substances such as pH adjusting buffering solutions (see page 54, lines 18-31). While Panousis et al does not disclose of the specific pharmaceutical formulations, one would modify the invention of Panousis with the high concentration formulations of Demopulos et al because Demopulos et al indicate that their claimed formulation demonstrated enhanced stability, especially at pH between pH 5 and pH 6. Thus, one would have a reasonable expectation that formulating the anti-factor XII/XIIa antibodies of Panousis with the formulations disclosed by Demopulos et al would optimize the stability of the pharmaceutical composition at 20°C (see MPEP 2144.05(II)(A) and 2144.05(II)(B)).
Conclusion
No claims are allowed.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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