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 .
Election/Restrictions
Applicant’s election of Group 1 (claims 101-105, 109, and 112-117) and amino acid sequence of SEQ ID Nos: 1-4 in the reply filed on 12/1/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The requirement is still deemed proper and is therefore made FINAL.
Status of Application, Amendments, And/Or Claims
Claims 101-120 are pending.
Claims 106-108, 110-111, and 118-120 are withdrawn for being drawn to nonelected inventions (i.e., Groups 3-5).
Claims 101-105, 109 and 112-117 are under consideration.
Priority
The instant application is a 371 of PCT/US21/19213 filed on 2/23/2021.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) filed on 3/3/2023, 10/9/2024,4/30/2025 and 6/9/2025 have been considered.
Claim Objections
Claims 109 and 112 are objected to because of the following informalities: claim 109 depends from claim 108 of non-elected invention of Group 2. Claim 112 depends from claim 111 of Group 3. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 103-105, and 109 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 written description in this case only sets forth a antibody that specifically binds to human endothelial lipase comprising amino acid a heavy chain of SEQ ID NO:4 and a light chain of SEQ ID NO:8, and therefore the written description is not commensurate in scope with “any antibody that specifically binds to endothelial lipase having only a first heavy chain CDR1 having at least 80% sequence identity to SEQ ID NO:1, or a second heavy chain CDR2 having at least 90% sequence identity to SEQ ID NO: 2 or a third heavy chain CDR3 having at least 90% sequence identity to SEQ ID NO: 3”.
The instant claims are directed to an “a pharmaceutical composition comprising an antibody that specifically binds to human endothelial lipase but requires to have the said antibody a single CDR of SEQ ID NO: 1, 2, or 3; or a single heavy chain of SEQ ID NO: 4 and each of them can vary up to 10% or 20%”. Making a polyclonal antibody against a polypeptide is well known in the art. The specification at pg. 13-15 discloses an antibody MEDI5884 that comprises variable heavy chain VH CDR1-3, having SEQ ID Nos: 1-3 (Table 1), and variable light chain, having SEQ ID Nos:5-7 (Table 2).
Chamow and Ashkenazi state on page 52, 1st paragraph (TIBTECH 14: 52-60, 1996) teach that making human monoclonal antibodies (mAbs) which are suitable for therapeutics are difficult for two reasons. First, humans are generally tolerant to their own antigens. Second, ethical considerations place restrictions on the active immunization of humans for the purpose of generating mAbs. They suggest that alternative technologies have been used to generate mAbs for therapeutic purposes, such technologies are (i) to produce chimeric or humanized antibodies, (ii) to select antibodies from phage display library, (iii) to generate human antibodies in animals such as mice by replacing the genetic loci for endogenous antibodies with gene elements for human antibodies, and (iv) to generate an antibody like molecule by combining framework sequences from a human mAb with sequences from a human protein that carries a target recognition function. Rudikoff et al. (Proc. Natl. Acad. Sci. 79: 1979-1983, 1982) teach that a large number of structural diversity can be generated from the germ line repertoire because more than 200 light (L) and heavy (H) chain gene exist in the germ line. They disclose that a single amino acid mutation in antigen can result in different antibody generation with different specificities and one CDR would not be enough for the antigen recognition. An antibody would need 6 CDRs to recognize the antigen with high specificity.
However, the prior art also recognizes that a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For example, Edwards et al. (2003, JMB 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDRS3 region sequences (that are generated by VDJ germline segment recombination) as well, (see table 2, figure 2).
The specification fails to provide a written description of the genus of antibodies that can specifically bind endothelial lipase having only a single defined CDR having amino acid sequence of SEQ ID NO: 1, 2 or 3 or having only a heavy chain on SEQ ID NO: 4. The specification does not disclose a genus of antibodies in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. The instant specification fails to describe any antibodies which only possess 1 of the necessary CDRs or mix and match CDRs and/or heavy/light variable chains and specifically binds human endothelial lipase as required by the claims, and there is no direction provided in the instant specification as to what additional structure would be required in order to obtain an antibody with the necessary binding characteristics and functional characteristics recited in the claims. The specification does not disclose a genus of antibodies comprising only a single CDR of SEQ ID NO: 1, 2 or 3 can specifically bind to human endothelial lipase. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1 "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
Vas-Cath Inc. V. Mahurka, 19 USPQ2d 1111, states 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, for purposes of the written description inquiry, is 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).
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B (1), the court states an adequate written description of a DNA ... 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.
As discussed above, the skilled artisan cannot envision the detailed genus of “an antibody (5884) that specifically binds endothelial lipase having a variable heavy chain and a variable light chain” and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of making a mutation. The compound itself is required. See Fiers v.Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen v.Baird, 30 Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 148 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class.
Therefore, the claim do not meet the written description provision of 35 U.S.C. §112, first paragraph.
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
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.
Claim(s) 101-105, 109, and 112-117 are rejected under 35 U.S.C. 103 as being unpatentable over Naito et al (US Pub. No. 2017/0260290, also published as US Pat. No. 10,570,215) in view of Partridge et al. (IDS, Pharm. Res. (2019) 36-71) as evidenced by Liu et al. (IDS, US Pub. No. 20120064086).
The instantly claimed invention is broadly drawn to a pharmaceutical formulation comprising:(i) about 40 mg/mL to about 160 mg/mL of an antibody that specifically binds to human endothelial lipase, and (ii) about 50 mM to about 260 mM arginine salt (claims 101-102), wherein the antibody that specifically binds endothelial lipase has a first heavy chain complementarity determining region (CDR1) with an amino acid sequence at least 80% identical to SEQ ID NO: 1 (claim 103), wherein the antibody that specifically binds endothelial lipase has a second heavy chain complementarity determining region (CDR2) with an amino acid sequence at least 90% identical to SEQ ID NO: 2 (claim 104), wherein the antibody that specifically binds endothelial lipase has a third heavy chain complementarity determining region (CDR3) with an amino acid sequence at least 90% identical to SEQ ID NO: 3 (claim 105), wherein the heavy chain of the antibody that specifically binds to endothelial lipase comprises an amino acid sequence at least 90% identical to SEQ ID NO: 4 (claim 109), wherein the formulation further comprises histidine (claim 112), wherein the pH is less than 7.0 (claim113), wherein the is suitable for a route of administration selected from the group consisting of intravenous injection, subcutaneous injection and intramuscular injection ( claim 116) and wherein the formulation is reconstituted from a lyophilized formulation (claim 116).
Naito et al. teach a humanized monoclonal antibody or a fragment thereof that selectively inhibits the enzymatic activity of endothelial lipase and a pharmaceutical composition containing the same as an active ingredient for treatment of atherosclerosis or metabolic syndrome (abstract, col. 1, lines 29+). Regarding claim 103, Naito et la teach an antibody having a CDR having amino acid sequence of SEQ ID NO: 25 which is 100% identical to the instantly claimed CDR1 of SEQ ID NO: 1 (see search result 1, US-17-801-670-1.rai). Regarding claim 104, Naito et la teach an antibody having a CDR having amino acid sequence of SEQ ID NO: 106 which is 100% identical to the instantly claimed CDR1 of SEQ ID NO: 2 (see search result 1, US-17-801-670-2.rai). Regarding claim 105, Naito et la teach an antibody having a CDR having amino acid sequence of SEQ ID NO: 24 which is 100% identical to the instantly claimed CDR1 of SEQ ID NO: 3 (see search result 1, US-17-801-670-3.rai). Regarding claim 109, Naito et al teach an antibody having a heavy chain variable amino acid of SEQ ID NO: 75 which is 100% identical to the instantly claimed heavy chain variable amino acid sequence of SEQ ID NO: 4 (see sequence result 1, US-17-801-670-4.rai and sequence alignment below). Naito et al do not teach that the composition comprises the antibody at about 40 mg/ml to about 160 mg/ml and arginine salt in about 50 mM to about 260 mM, and the composition further comprising histidine, wherein the pharmaceutical composition is reconstituted from a hydrolyzed formulation, and the formulation is suitable for administration for the group consisting of intravenous injection, subcutaneous injection and intracellular injection.
Partridge et al. making a composition comprising an antibody reconstituted from a lyophilized sample, wherein the antibody is 20 mg/mL to about 150 mg/mL (see Table 1 and pg. 18 of 21, (Conclusion and outlook)). They teach that the antibody is reconstituted in 80 mM arginine HCL, 120 mM sucrose and 20 mM histidine/histidine HCl (pg. 3, left col.). Regarding claim 113, they teach that the pH of the antibody buffer is 6 (which is less than pH 7). They teach reconstitution of antibody from lyophilized sample and study time needed for reconstitution. The resuspended sample would be suitable for administration to a subject by subcutaneous route. Additionally, because the antibody constituted from the lyophilized sample meets the limitation of claim 101, the composition would have viscosity of <= 30 cP at 18 °C and would have osmolality of about 260-500 mOsm/kg, unless evidence to contrary. Liu et al teach a stable formulation of an antibody having low turbidity and high concentration (title, abstract). They teach that the antibody can be in a range of 100-260 mg/ml, arginine HCl in an amount of 50-260 mg/ml, histidine 10-100 mM, polysorbate 0.01-0.1% wherein the pH is about 5.5 to 7.0, and kinetic viscosity is 50 cs or less and osmolarity is 200 -450 mOsm/kg (abstract, paragraph [0012]). Therefore, the formulation would be suitable for subcutaneous injection (as stated in the abstract by Liu et al).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use a lyophilized composition of an antibody to reconstitute in arginine HCl having concentration of 50-260 mM and wherein the antibody is about 25-150 mg/mL as taught by Partridge et al. for an antibody that specifically binds to human endothelial lipase as taught by Naito et al. Partridge et al teach a lyophilized antibody in composition having 80 mM arginine HCl and histidine wherein the composition has pH 6.0 which would be suitable for subcutaneous administration and would have cs less than 50 as evidenced by Liu et al. Additionally, one would have been motivated to do so because Partridge et al. teach reconstitution of a lyophilized protein or an antibody from a lyophilized sample wherein the reconstitution is in 80 mM arginine HCl, histidine and the pH of the composition is 6.0. Further, one would have a reasonable expectation of success in using the antibody taught by Naito which specifically binds to human endothelial lipase and comprises the instantly claimed heavy chain amino acid sequence of SEQ ID NO: 4 and prepare a lyophilized sample for a long term storage that can be reconstituted in arginine HCl as taught by partridge. Therefore, the instantly claimed invention would have been obvious over the combined teachings of the prior art.
“Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." See In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989); see also MPEP §716.02(c). Additionally, “[it] is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) and MPEP § 2144.06.
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Conclusion
No claim is allowed.
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/GYAN CHANDRA/Primary Examiner, Art Unit 1674