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 .
DETAILED ACTION
The amendment filed January 26, 2026 in response to the Office Action of August 12, 2025 is acknowledged and has been entered.
Claims 1 and 18 have been amended.
Claim 19 has been cancelled.
Claim 20 has been added.
Claims 1, 6, 18 and 20 are pending and under consideration.
The 112(a) Written Description rejection for claim 18 is hereby withdrawn in view claim amendments and applicant’s arguments.
Double Patenting rejection over Pat. 10,081,680 is hereby withdrawn in view of claim amendments and applicant’s arguments.
MAINTAINED/MODIFIED REJECTIONS
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 1 and 6 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. This is a WRITTEN DESCRIPTION rejection.
The rejected claims are drawn to a method of inducing phagocytosis of a CD24-expressinq target cell, the method comprising: contacting the target cell with a macrophage in the presence of an anti-CD24 antibody for a period of time sufficient to induce phagocytosis of the target cell by a macrophage, wherein the contacting is in vivo, and wherein the anti-CD24 antibody is ML5 or a variant thereof, and wherein the variant comprises at least a single variable region framework residue insertion, deletion, or substitution, …, and the anti-CD24 antibody comprises a light chain comprising a set of 3 light chain CDR sequences and a heavy chain comprising a set of 3 heavy chain CDR sequences. Based on paragraph [0013] of the instant publication US 2021/0213055A1: variant of an anti-CD24 antibody would encompass “In some embodiments the anti-CD24 antibody comprises at least one, usually at least three CDR sequences from a set, ..., In other embodiments, the antibody comprises an amino acid sequence variant of one or more of the CDRs of the provided antibodies, which variant comprises one or more amino insertion(s) within or adjacent to a CDR residue and/or deletion(s) within or adjacent to a CDR residue and/or substitution(s) of CDR residue(s) … The antibody may be a full length antibody, …, or an antibody fragment”. Given Broadest Reasonable Interpretation (BRI), variant of ML5 wherein the variant comprises at least a single variable region framework residue insertion, deletion, or substitution; and the anti-CD24 antibody comprises a light chain comprising a set of 3 light chain CDR sequences and a heavy chain comprising a set of 3 heavy chain CDR sequences would still encompass a very large genus of antibody variants, including antibody variants which do not comprise complete CDR set (HCDRs1-3 and LCDRs1-3) of ML5, because the variants can have any number of insertions, deletions or substitutions in the CDR regions. These antibodies would vary significantly, and would have different structures and properties.
The instant specification discloses only three full length anti-CD24 antibodies: SN3, ML5 and AB1. Among them, the instant specification shows that SN3 can induce phagocytosis of CD24+ cancer cells in vitro (Figs. 4A-C, [0184], Example 1; Figs. 6 and 7, [0196], [0197], Example 2) or in vivo (Fig. 14, [0224-0226], Example 2). Weiskopf (Weiskopf et al., The Journal of Clinical Investigation, 2016, 126(7): 2610-2620, with supplementary materials, Publication Date: July, 2016, of record) shows that antibody ML5 can induce phagocytosis of CD24+ cancer cells in vitro (see more in 103 rejection below). The instant specification does not show claimed activity (inducing phagocytosis) any variant of ML5 encompassed by the claims have claimed properties, e.g. inducing phagocytosis of the CD24 targeting cells, in vitro or in vivo. Thus, these claims lack written description because the specification lacks a representative number of species that satisfies the entirety of the genus.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. (See Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, especially page 1106 3rd column). A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. MPEP 2163 II.A.3a.ii.
MPEP 2163 II A 3(a) states: Disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
As was well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CHI, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level. By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Fransson, Frontiers in Bioscience 2008; 13: 1619-33 (see Section 3) "Antibody Structure and the Antigen Binding Site" and Figure I, of record).
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses one full length monoclonal antibody (SN3) specific to CD24 with claimed activities to CD24+ cancer cells. Prior art provides support to full length antibody ML5. However, antibody variants encompassed by the claims would have been generally expected to be highly structurally diverse, particularly in the CDR sequences. Thus, applicants have not disclosed species sufficient to describe the claimed genus of antibody variants specific to CD24 with claimed properties.
To provide adequate written description and evidence of possession of the
claimed antibody genus, the instant specification can structurally describe representative antibodies specific to CD24 that have claimed properties: induce phagocytosis of a target cell (e.g. a cancer cell) by macrophage, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics,
functional characteristics when coupled with a known or disclosed correlation between
function and structure, or some combination of such characteristics (see University of
California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and
Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe
a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to produce and screen for
ML5 variants having claimed properties, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n 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.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The antigen, CD24, provides no information about the structure of an antibody that has immunological reactivity as claimed.
In this case, the instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose a single exemplary antibody variants that functions as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. The specification fails to provide any structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody variants for the genus of antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
Given the lack of representative species to support the full scope of the claimed antibody variants required to practice the claimed method, and lack of reasonable structure-function correlation with regards antibody variants that provide claimed activity/function, the present claims lack adequate written description.
Response to Arguments
For the rejection of claims 1 and 6 under 35 U.S.C. 112(a), Applicant argues:
With regard to variants of the ML5 antibody, the amended claims state that the variant
antibody comprises a light chain having 3 CDRs and a heavy chain having 3 CDRs. Thus, the claimed method uses an antibody that has a complete set of CDRs and does not encompass antibodies with partial CD Rs as stated by the Office (OA pg. 10). The amended claims also state that the variant antibody has at least a single variable region framework residue insertion, deletion, or substitution indicating that the variant antibody may have a different variable heavy region framework than that of the ML5 antibody. It is well known in the art that CDR sequences may be swapped between different frameworks and still retain binding activity. For instance, Willida et al. (Cancer Res. 1999 Nov 15;59(22):5758-67) grafted the CDRs of an scFv that had a high binding affinity for epithelial glycoprotein-2 but had a low thermal stability into the framework of an scFv that had a high thermal stability and was able to retain the binding affinity to epithelial glycoprotein-2. Similarly, Riechmann et al. (Nature. 1988 Mar 24;332 (6162):323-7. doi: 10.1038/332323a0) and Verhoeyen et al. (Science. 1988 Mar 25;239 (4847):1534-6) have shown that CDRs from rat and mouse antibodies, respectively, can be swapped into human frameworks and still retain their binding activity. Accordingly, it was well known in the art at the time of filing that antibodies can retain their binding activities when their frameworks are changed.
Additionally, it is also known in the art at the time of filing that framework regions of
antibodies have a high tolerance for mutations that allow antibodies to retain their binding
activities. For instance, Koenig et al. (Proc Natl Acad Sci USA. 2017 Jan 24;114(4):E486-E495) is a study directed to deep mutational scanning to dissect how mutations in all positions of the
variable domain of an anti-VEGF antibody impact antigen binding. Specifically, Koenig generated a phage display library of VEGF Fab variants with all possible single mutations through the variable HC (VH library) and LC (VL library) domains and compared the frequency of each mutation in the library before and after selection for binding. When describing the results, Koenig states "The resulting mutational landscape demonstrates that large portions of antibody variable domain positions are open to mutation, and that beneficial mutations can be found throughout the variable domains ... We found that a large number of single mutations in the framework outside the structural core and the VH-VL interface are well tolerated." (Abstract and pg. E487 pt column pt paragraph; emphasis added) Accordingly, Koenig teaches that antibodies are tolerant of variants in the framework while still retaining binding activity. In view of the above, the skilled artisan would understand that variants of MLS having changes in the framework would retain their binding activity and that the inventors were in possession of claimed invention at the time of filing at least because antibodies have been shown to retain activity following the complete swapping of frameworks or with mutations with the framework region.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, although the amended claims recites: “wherein the variant comprises at least a single variable region framework residue insertion, deletion, or substitution; … and the anti-CD24 antibody comprises a light chain comprising a set of 3 light chain CDR sequences and a heavy chain comprising a set of 3 heavy chain CDR sequences, given BRI, the claims still encompass antibodies with CDRs different from CDRs of antibody ML5. By using “comprises”, the antibody variants could have any number of insertions, deletions, or substitutions in the CDR regions. The specification and prior art only describe two full length antibodies: SN3 and ML5 with required activity: inducing phagocytosis. The specification and prior art does not disclose any ML5 variants have the required properties to be used in the claimed method. Furthermore, the specification fails to provide any structural features coupled to the claimed functional characteristics. Accordingly, one of ordinary skill in the art would not be able to readily visualize/recognize the structure of any other antibody or variant with claimed properties, except antibodies with the same CDR combinations as ML5. Therefore, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method. The rejection maintained for the reasons of record.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6, 18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Weiskopf (Weiskopf et al., The Journal of Clinical Investigation, 2016, 126(7): 2610-2620, with supplementary materials, Publication Date: July, 2016, of record).
Weiskopf teaches macrophages are present in SCLC tumors in vivo (page 2612, col. 1, para. 2).
Weiskopf teaches that CD24 is expressed on the surface of SCLC cells (page 2616, col. 1, para. 1).
Weiskopf teaches antibody to CD24 alone was able to induce phagocytosis of NCI-H82 and NCI-H524 cells that was compared to or exceeded that of treatment with anti-CD47 antibody (page 2617, col. 1 and Figs. 6C and 6D). Antibody to CD24 alone would read on the limitation “not administrated in combination with an anti-CD47/SIRPα agent”.
Weiskopf teaches that the anti-CD24 antibody is ML5 (§ Therapeutic reagents, on page 2 of Suppl.).
Weiskopf teaches that NCI-H82 and NCI-H524 are two different SCLC (small cell lung cancer) cells (page 2616, col. 2, para. 2).
Weiskopf teaches that the phagocytosis reaction were carried out using macrophages and tumor cells (page 4, para. 1 of Supplementary Materials).
Weiskopf further teaches that CD24 highly expressed on the surface of SCLC cells and could potentially be targeted by monoclonal antibody therapies (page 2616, col. 1, para. 1).
Taken together, Weiskopf teaches that administering CD24 antibody alone (e.g. ML5) can induce phagocytosis of CD24 expressing cancer cells (e.g. SCLC cancer cells). Although Weiskopf does not explicitly teaches contacting a target cell with anti-CD24 antibody in vivo, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the antibody for in vivo application, because ML5 shows good activity for inducing phagocytosis of CD24 expressing SCLC cancer cells in vitro, and the CD24 antigen SCLC cells in vivo, as taught by Weiskopf. One of ordinary skill in the art would have had a reasonable expectation that the anti-CD24 antibody (ML5) could induce phagocytosis in vivo based on the in vitro results and would be able to induce phagocytosis of SCLC cancer cells in vivo. Given that the ML5 antibody has been known in the art, as evidenced by the reference, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention. The motivation would be to develop a new method with a well-known compound (ML5) for inducing phagocytosis of CD24 expressing cancer cells in vivo.
Regarding claim 20, ML5 antibody would comprise the set of 3 light chain CDR sequences and the set of 3 heavy chain CDR sequences of the ML5 light chain and heavy chain CDR sequences
Response to Arguments
For the rejection of claims 1, 6, and 18 under 35 U.S.C. 103 as being unpatentable over Weiskopf, Applicant argues:
Weiskopf is directed to developing monoclonal antibody treatments to be used in combination with CD47 blocking therapies. All throughout Weiskopf's disclosure CD47 is the central focus. For instance, the title refers "CD47-blocking immunotherapies", the abstract states "In light of recent clinical trials for CD47-blocking therapies in cancer treatment, these findings identify disruption of the CD47/SIRPa axis as a potential immunotherapeutic strategy for SCLC" and the end of the introduction "Since no therapeutic antibodies have been approved for SCLC, we aimed to identify antigens on the surface of SCLC cells and target them with monoclonal antibodies in combination with CD47-blocking therapies to achieve maximal antitumor responses against SCLC." (pg. 2612 ist column ist paragraph). Accordingly, the entire focus of Weiskopf is directed to the usage of CD47-blocking therapies.
Weiskopf only contains a single section that is directed to the identification of other cell surface targets to be used in combination with a CD47-blocking therapy. The section referring to the combination treatment is entitled "Combining antibodies with CD47 blockade enhances phagocytosis of SCLC" (pg. 2616), and the section concludes by stating "Thus, combining therapeutic antibodies with CD47-blocking strategies may represent an alternative method for enhancing the efficacy of antibodies" (pg. 2618 ist column 2nd paragraph; emphasis added). Even the end of the discussion section specifically calls combination therapies when stating "These cocktails could be combined with CD47-blocking therapies and other immunotherapies or targeted therapies (53) to mount an effective immune response against cancer cells." (pg. 2619 ist column 2nd paragraph; emphasis added) Applicant submits that the skilled artisan looking to Weiskopf would not be motivated to modify Weiskopf to use an anti-CD24 antibody in vivo in the absence of a CD47-blocking agent at least because the entire disclosure of Weiskopf is directed to the use of a CD47-blocking agent by itself or combination with a monoclonal antibody and provides no suggestion of a treatment in the absence of a CD47-blocking agent.
Applicant’s arguments have been fully considered but they are not persuasive. Contrary to Applicant’s argument that Weiskopf only teaches combination application with a CD47-blocking agent, Weiskopf clearly teaches using anti-CD24 antibody (ML5) alone can induce phagocytosis of two different SCLC cancer cells in vitro (see Fig. 6C and 6D). Fig. 6D clearly shows that antibody to CD24 alone was able to induce phagocytosis of NCI-H82 and NCI-H524 cells that was compared to or exceeded that of treatment with anti-CD47 antibody (page 2617, col. 1 and Figs. 6C and 6D). Thus, based on the in vitro data, one of ordinary skill in the art would have reasonably expected that the antibody to CD24 alone (such as ML5) would be able to induce phagocytosis of SCLC tumor cells expressing CD24 in vivo. One of ordinary skill in the art would have been motivated to develop a new and simple method for treating SCLC with a well-known compound.
Furthermore, In the field of biological technology, no invention has absolute certainty of success before experimental tests. Thus, only a reasonable expectation of success (not absolute) would have motivated an artisan to make the claimed method. Given the teachings from Weiskopf, an ordinary skilled in the art would have would have had a reasonable expectation of success in producing the claimed invention.
Thus, the rejection is maintained for the reasons of record.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642