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 .
Response to Amendment
The rejections of claims 7 and 8 are moot in view of the cancellation of the claims.
The rejection of claims 4 and 6 under 35 USC 112(b) are withdrawn in view of the amendment to claim 4 clarifying the binding is to the extracellular matrix domain of PECAM1 and claim 6 clarifying the grammatical numbers of the terms in the claim. Note a new rejection of amended claim 4 appears below.
The rejection of claims 4-6 under 35 U.S.C. 102(a)(1) as being anticipated by CN 108588033 (CN’033, published 28 Sept. 2018) in light of US 10,775,387 B2 is withdrawn in view of the amendment to claim 4 bringing in the limitation from claim 7.
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 4 and 5 and dependent claim 6 are or remain 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.
Amended claim 4 recites the limitation "the separated antibodies" in the last line. There is insufficient antecedent basis for this limitation in the claim. The claim only recites separation of a single antibody not plural antibodies.
Amended claim 5 is indefinite because it recites the vector contains an amino acid encoding… Vectors do not comprise amino acids and amino acids do not encode a protein. This rejection could be obviated by deleting “contains an amino acid” if appropriate. For the purpose of compact prosecution, it will be assumed it was meant that the vector encodes the extracellular matrix domain of the PECAM1.
Claim 5 remains rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: the step of producing/expressing the protein containing the extracellular matrix domain (EMD) of the PECAM1. The steps of the claim jump from transfecting a host cell with a plasmid to obtaining the protein containing the EMD of the PECAM1. This rejection could be obviated by including the step of expressing the EMD of the PECAM1 from the host cell (see p. 20, lines 23-24).
Applicant argues (p. 2, middle, of Remarks filed 7/21/2025, corresponds to p. 13 of full response) that the amendments to the claims address the issues of the rejection and overcome the rejections under 35 USC 112(b). The argument has been fully considered but is not persuasive. While the amendment to the claims overcomes most of the previous rejections, it does not overcome all and precipitated new rejections as set forth above.
Priority
Applicant cannot rely upon the certified copies of the foreign priority applications to overcome this rejection because a translation of said applications has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
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.
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.
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) 4-6 remain rejected under 35 U.S.C. 103 as being unpatentable over CN 108588033 (CN’033) as applied to claims 4-6 and 8 above, and further in view of Kang et al. (BioProcess Intl., Retrieved online: <URL:https//bioprocessintl.com/manufacturing/
formulation/rapid-formulation-development-formonoclonal-antibodies/>, [retrieved on 04 Nov 2019] April 2016.) for the reasons set forth in the previous Office action and recast here to better address the amendment to the claims.
CN’033 teaches making an antibody that binds CD31 (PECAM, platelet endothelial cell adhesion factor-1) and that recognizes vascular endothelial cells (first and second paragraphs of “Background, p. 1/7 of Description, English translation). It is taught for preparation of a CD31 monoclonal antibody that BALB/C mice are immunized by injection of the extracellular domain of recombinant CD31, wherein the CD31 is produced by recombinant expression from engineered cells (p. 2/7, step (1)). The B lymphocyte of the animal after immunization is fused to a myeloma cell and cultured (p. 2/7, (step 2)). The positive clone is determined which stably secretes a CD31 monoclonal antibody (mAb) determined by ELISA (p. 2/7, step (3)). The CD31 monoclonal antibody is obtained (p. 2/7, step (4)). (See also p. 2/7, third to last full paragraph-Fig. 1A-C description.) Multiple positive clones were obtained, with clone 4H3 producing the best antibody (p. 2/7, Brief Description of Figs. 1A-C and Figs. 2A-C, also describing 4H3 mAb). More detailed descriptions are provided beginning on p. 3/7 under “Example 1 Preparation of CD31 Monoclonal Antibody”. The CD31 mAb is described as having higher accuracy, higher titer, higher positive intensity than the common antibody on the market (p. 2/7, ~2/3 the down the page). Fig. 3 shows that the monoclonal antibody binds epithelium-like vascular sarcoma tissue (end of p. 2). CN‘033 does not teach wherein the antibody concentration is 3.5 mg/ml.
Kang et al. teaches antibody formulations and that for 37 analyzed commercial antibodies, concentrations ranged from 2 mg/ml to 200 mg/ml (p. 2/7, first full paragraph).
It would have been obvious wherein the concentration of the separated antibody 4H3 of CN’033 was at least 3.5 mg/ml because this is at the very lower range of concentrations of commercial antibodies and the disclosed CD31 mAb was described as higher titer than the common commercial antibody. It would also have been obvious wherein the concentration of the other CD31-specific antibodies of CN’033 was at least 3.5 mg/ml.
Claim(s) 4-6 remain rejected under 35 U.S.C. 103 as being unpatentable over US Patent 7,572,443 B2 (‘443) in view of US Patent 10,775,387 (‘387), US Patent 8,377,448 B2 (‘448), US Patent 9,127,070 B2 (‘070) and Kang et al. (BioProcess Intl., Retrieved online: <URL:https//bioprocessintl.com/manufacturing/
formulation/rapid-formulation-development-formonoclonal-antibodies/>, [retrieved on 04 Nov 2019] April 2016.) for the reasons set forth in the previous Office action as a recast here to better address the amendment specifying the positive clone binds the extracellular matrix domain of the PECAM1 (claim 4).
US 7,572,443 teaches in col. 12, lines 46-61, that an anti-PECAM-1 antibody can be produced by injecting into a mouse a recombinantly produced fragment of PECAM-1 along with an adjuvant by following immunization protocols known to those of skill in the art so as to generate an immune response to produce antibodies that can bind native human PECAM-1 polypeptide. PECAM-1 is also called CD31 or PECAM (e.g., col. 1, lines 65-66). To produce an anti-PECAM antibody, spleen cells from the immunized animal are fused to myeloma cells to produce hybridoma cells that can be screened for anti-PECAM-1 antibody-secreting clones (col. 12, line 65, through col. 13, line 2). It is taught human PECAM-1 may be recombinantly produced by inserting the encoding gene into a suitable DNA vector, such as a bacterial plasmid, and transforming a suitable host cell (col. 8, lines 31-40). The inventor found that anti-PECAM antibody reduced the tumor burden in lungs of a metastatic mouse melanoma model (Figs. 1B, 2B, 3B and 4B) and in human LOX melanoma xenograft tumor nude mice (Fig. 5B; col. 18, line 3, through col. 29, line 19). The sequence of the PECAM-1 is not taught, nor that the spleen cells are B lymphocytes. The concentration of separated antibodies is not taught.
US 10,775,387 teaches antibodies that bind the ECD of CD31, e.g., binding an epitope within the Ig-like domain 6 (e.g., col. 3, lines 29-33) or within Ig-like domains 1-5 (col. 6, lines 14-16). The sequence of the full-length membrane-spanning human CD31 is set forth in SEQ ID NO:1, with the extracellular domain (ECD) of amino acids 28-601, which comprises 6 Ig-like domains (col. 7, lines 52-57, and Table 1). The patent discloses antibodies to different regions of the CD31 ECD that can aid in the detection of different soluble forms (e.g., col. 1, lines 27-43).
US 8,377,448 teaches monoclonal antibodies that bind the extracellular domain of CD47, such as those produced by immortal eukaryotic cell lines which were old in the art (col. 43, lines 9-25). An animal, e.g., a mouse, is immunized with the CD47 immunogen by injection (col. 43, lines 25-35). As stated in col. 43, line 64, through col. 44, line 18):
From animals producing specific antibodies, lymphoid cells (most commonly cells from the spleen or lymph node) are removed to obtain B-lymphocytes, which are lymphoid cells that are antibody-forming cells. The lymphoid cells, typically spleen cells, may be immortalized by fusion with a drug-sensitized myeloma (e.g., plasmacytoma) cell fusion partner, preferably one that is syngeneic with the immunized animal…. The lymphoid cells and the myeloma cells may be combined for a few minutes with a membrane fusion-promoting agent, such as polyethylene glycol or a nonionic detergent, and then plated at low density on a selective medium that supports the growth of hybridoma cells, but not unfused myeloma cells. A preferred selection media is HAT (hypoxanthine, aminopterin, thymidine). After a sufficient time, usually about one to two weeks, colonies of cells are observed. Antibodies produced by the cells may be tested for binding activity to the antigen. The hybridomas are cloned (e.g., by limited dilution cloning or by soft agar plaque isolation) and positive clones that produce an antibody specific to the antigen are selected and cultured. Hybridomas producing monoclonal antibodies with high affinity and specificity for the CD47 extracellular domain are preferred. Similarly, hybridomas producing monoclonal antibodies with high affinity and specificity for the CD47 ligand, particularly, the extracellular domain, are preferred.
Monoclonal antibodies may be isolated from the supernatants of hybridoma cultures…. For example, antibodies may be purified by affinity chromatography using an appropriate ligand selected based on particular properties of the monoclonal antibody (e.g., heavy or light chain isotype, binding specificity, etc.). Examples of a suitable ligand, immobilized on a solid support, include Protein A, Protein G, an anti-constant region (light chain or heavy chain) antibody, an anti-idiotype antibody, the CD47 extracellular domain or fragment thereof.
“In general, an immune response includes (1) a humoral response, in which antibodies specific for antigens are produced by differentiated B lymphocytes known as plasma cells…” (col. 26, lines 37-40) It is taught that expression vectors, e.g., plasmid vectors, may be used to produce a CD47 ECD fusion polypeptide. Host cells transfected with the vector are then cultured to produce the protein (col. 64, lines 1-15 and 51-58). Detailed purification of the fusion is described in col. 90, lines 34-54.
US 9,127,070 teaches monoclonal antibodies that bind the extracellular domain of DR5. A method of producing an antibody by establishing a hybridoma were old and known in the art (col. 16, lines 15-21). It teaches the antigen for immunization may be obtained by expressing an encoding nucleic acid in a vector transfected into a host cell or secretion from a host cell comprising a vector with a nucleic acid encoding the ECD of DR5, which is a membrane-spanning protein, joined to an antibody constant region (col. 15, lines 41-52). Methods of purification of the encoded ECD produced either way is set forth in col. 16, lines 14-42. The method of producing the antibody is described as (col. 16, lines 48-67):
The production of a monoclonal antibody generally requires the following operational steps of:
(a) purifying a biopolymer to be used as an antigen;
(b) preparing antibody-producing cells by immunizing an animal by injection of the antigen, collecting the blood, assaying its antibody titer to determine when the spleen is to be excised;
(c) preparing myeloma cells (hereinafter referred to as "myeloma");
(d) fusing the antibody-producing cells with the myeloma;
(e) screening a group of hybridomas producing a target antibody;
(f) dividing the hybridomas into single cell clones (cloning);
(g) optionally, culturing the hybridoma or rearing an animal implanted with the hybridoma for producing a large amount of a monoclonal antibody;
(h) examining the thus produced monoclonal antibody for biological activity and binding specificity, or assaying the same for properties as a labeled reagent; and the like.
Specifically, spleen cells or lymphocytes comprising the antibody producing cells are removed and separation of the antibody producing cells from the spleen or lymphocytes is conducted by known methods old in the art (col. 17, lines 62-67). The selected hybridoma is cultured and the hybridoma producing the DR5 monoclonal antibody is determined ( col. 18, lines 44-67). The antibody produced thereby is purified (col. 20, line 16-40). Example 1 further describes both recombinant production of the human DR5 ECD-Fc fusion antigen as well as antibody production through immunization.
Kang et al. teaches antibody formulations and that for 37 analyzed commercial antibodies, concentrations ranged from 2 mg/ml to 200 mg/ml (p. 2/7, first full paragraph).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the invention to have produced an antibody that bound the ECD of PECAM-1 (CD31) by methods well known and old in the art to obtain antibodies with antitumor therapeutic potential as well as to identify different soluble PECAM-1 forms (see ‘443 and ‘387). Using such methods, it would have been obvious to one of ordinary skill in the art to have produced a human PECAM-1 antigen by preparing a recombinant plasmid vector encoding the ECD of human PECAM-1 as disclosed by ‘448 and ‘070 for ECDs of CD47 and DR5, respectively, and PECAM-1 as taught by ‘443. It further would have been obvious to inject the PECAM-1 ECD antigen into an animal for production of antibodies using the methods of ‘448, ‘443 and ‘387, which were recognized as known and old in the art. Such methods involve injecting into an animal capable of producing antibodies a protein comprising the ECD of the antigen, in this case the ECD of human PECAM-1, i.e., as disclosed by ‘387, followed by determination of a positive cellular clone from the animal that recognizes the PECAM-1 ECD, and purifying the anti-PECAM-1 antibody from the positive clone (see especially the known method described by ‘448 and ‘070). It would have been obvious wherein the epitope bound by the antibody was within the Ig-like domain 6 (e.g., col. 3, lines 29-33) or within Ig-like domains 1-5 as taught by US 10,775,387. It would have been obvious wherein the positive clone was one of a plurality of B lymphocytes from the immunized animal, and wherein the positive clone(s) was fused to myeloma cells to produce antibody-expressing hybridoma cells, which hybridoma cells were cultured to allow determination of one or more positive clones that recognize human PECAM-1 ECD or portion thereof. ‘448 and ‘’070 teach known methods for separating and purifying a monoclonal antibody from the positive clone(s), for example, by assaying biological activity and/or binding specificity, e.g., by affinity column. There would have been a reasonable expectation that the concentration of the separated anti-human PECAM-1 ECD antibody was at least 3.5 mg/ml because this is at the very lower range of concentrations of commercial antibodies.
Note that in the instant claims neither the “protein containing an extracellular matrix domain of PECAM1” (claim 4) nor “vector [containing an amino acid] encoding the extracellular matrix domain of the PECAM1” (claim 5) excludes having more than the extracellular matrix domain of PECAM1 because the word “containing” is open, allowing from more than that which is recited, as opposed to the term “consisting of”. Also, the extracellular domain of PECAM-1 of ‘387, i.e., amino acids 28-601 of SEQ ID NO:1, is identical to instant SEQ ID NO:1 with the exception of a single amino acid substitution at position 518.
Both rejection under 35 USC 103 are addressed together in Applicant’s Remarks:
Applicant argues (p. 3, through top of p. 4 of Remarks) that none of the references teach “wherein a concentration of the separated antibodies against PECAM1 is at least 3.5 mg/ml”. “[T]he examiner does not provide specific reasons for the rejections as being unpatentable.” The argument has been fully considered but is not persuasive. This is not an anticipatory rejection, but one based on obviousness. It is maintained for the reasons for record that (end of first rejections), “It would have been obvious wherein the concentration of the separated antibody… was at least 3.5 mg/ml because this is at the very lower range of concentrations of commercial antibodies and the disclosed CD31 mAb was described as higher titer than the common commercial antibody.“ and (end of second rejection), “There would have been a reasonable expectation that the concentration of the separated… antibody was at least 3.5 mg/ml because this is at the very lower range of concentrations of commercial antibodies.” Further, claim 4 only requires “a concentration of the separated antibodies…is at least 3.5 mg/ml.” Concentrations can also be set by the practitioner depending on whether the antibody is further concentrated or diluted.
Applicant argues (p. 4, top through middle) CN ‘033 “merely teaches the general concept of using PECAM1 as an antigen and purifying antibodies.” It does not provide an express teaching or suggestion to use specifically the extracellular matrix domain (EMD) of SEQ ID NO:1 of the instant application, which discloses antibody generation using the defined 574-amino acid region to generate positive clones and a purified antibody at a final high concentration of at least 3.5 mg/ml. The argument has been fully considered but is not persuasive. First, it is important to note that claim 4 says protein administered for antibody production contained an EMD of PECAM1 having an amino acid sequence represented by SEQ ID NO:1. The words “containing” and “having” are both open and allow for additional matter, e.g., the signal peptide or transmembrane domain in addition to SEQ ID NO:1. Second, the 738 amino acid sequence of SEQ ID NO:1 of 10,775,387 represents the full-length PECAM1 protein, but ‘387 details in Table 1 that the ECD is amino acids 28-601, which differs by only a single amino acid from instant SEQ ID NO:1. As a results, antibody generation with the ECD of PECAM-1 (CD31) would have been reasonably expected to bind the extracellular matrix domain, which is identical or over 99% identical to of the ECD of PECAM1. Further, as discussed in the preceding paragraph, antibody concentration is determined not only by amount of antibody produced, but also by the dilution or concentrating thereof. There is no specific purification step in claim 4 that would make it unexpected to be able to reasonably produce an antibody concentration of the separated antibody that is at least 3.5 mg/ml. The specification only says (p. 9, line 25), “Antibodies against PECAM1 as obtained according to the method... may have a concentration of 3.5 mg/ml or greater.” While a working example supporting the limitation is in no way required, it is noted that there is no working example showing production and separation of the antibody (antibodies) at a concentration of 3.5 mg/ml or more or suggestion that it would require undue experimentation to do so.
Applicant argues (second half of p. 4, through top of p. 5) Kang only describes techniques for ‘formulating high-concentration antibody compositions’ but not a process for doing so. The other US Patent references do not disclose "a concentration of the separated antibodies against the PECAM1 is at least 3.5 mg/ml”. The argument has been fully considered but is not persuasive. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed in the immediately preceding paragraph, an EMD of PECAM1 having (i.e., comprising) SEQ ID NO:1, is the same as or >99% identical to the ECD of ‘387 and reasonably appears to the ECD of CN ‘033 also, absence evidence to the contrary. It is noted that US Patent 10,775,387, relied upon in the second rejection under 35 USC 103, taught antibodies binding an epitope within Ig-like domains 1-5 of PECAM1, which domains are inherently comprised by the EMD. Also, the concentration of the separated antibody is at least 3.5 mg/ml, which concentration is within the normal range of commercial antibodies (Kang) and the concentration of an antibody preparation may be changed by diluting or concentrating a purified/separated antibody. It is maintained for the reasons of record that the combination of prior art makes obvious a method of producing an antibody for purifying a vascular endothelial cell by the method of claim 4, including wherein a concentration of the separated antibody (antibodies) binding PECAM1 is at least 3.5 mg/ml.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
UniProt ID P16284 (https://www.uniprot.org/uniprotkb/P16284/entry#sequences, 2025) describes human PECAM1 (Protein names, third page). The extracellular domain is identified as amino acids 28-601, which contains Ig-like 1-6 domains, and is identical in size and sequence to instant SEQ ID NO:1 with the exception of a conservative amino acid substitution L98V (Subcellular Location:Features, Family & Domains:Features, and Sequence & Isoforms:P16284-1, pp. 5, 12 and 14, respectively). This is an evidentiary reference provided to show that the “extracellular domain” of PECAM1 is the same as the “extracellular matrix domain” of instant SEQ ID NO:1 and agrees with US 10,775,387 B2 relied upon in the rejection above.
Examiner’s Comment
Applicant’s request for a telephonic interview in the Remarks filed 7/21/2025 if the response does not place the application in condition for allowance is acknowledged. However, the Examiner determined that such an interview would not be productive in view of the rejections maintained and new rejections due to claim amendments. The Examiner has presented a full response to Applicant’s arguments for Applicant’s review.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
September 5, 2025