Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim status
The preliminary amendments filed on June 1, 2023 amended claims 5-7, 10, 14, 16, 19, 23, 27, 29, 41, 44-46, 48-49, and 53; canceled claims 2-4, 8-9, 15, 17-18, 24-26, 28, 30-40, 43, 50-52, and 55-66. Consequently claims 1, 5-7, 10-14, 16, 19-23, 27, 29, 41-42, 44-49, and 53-54 are pending and will be examined on the merits.
Priority
The instant application claims benefit of provisional applications, Application No. 63347647 (filed June 1, 2022). The effective filing date of instant claims 1, 5-7, 10-14, 16, 19-23, 27, 29, 41-42, 44-49, and 53-54 is June 1, 2022.
Specification
The use of trade names or trademarks used in commerce has been noted in this application. For example, “Adcetris” is a trade name which is accompanied by the generic terminology, Brentuximab Vedotin (paragraph [0538]), in the specification. 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.
The instant application recites tradenames of therapeutic agent used to treat cancer or a condition related to cancer without proper symbol indicating use in commerce such as ™, SM , or ® following the term in paragraph [0538] (page 49-50). Appropriate correction for the tradenames used in the specification of the instant case is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 7, 10-14, 16, 19-23, 27, 29, 44-45 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 claims contain 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.
Regarding claims drawn to a single light chain (Lc) or heavy chain (Hc) sequence without disclosure of their cognate Hc or Lc, respectively: claims 7, 10-14, 16, 19-23:
Claim 7 recites a light chain variable region (VL) of an antibody or antigen binding fragment without reciting a sequence or structure of a cognate Hc or heavy chain variable region (VH) that is compatible with the recited VL, such that when joined with the recited VL, the resultant antibody or antigen binding fragment possesses the recited function of binding to Claudin 18.2.
Similarly, claims 10-14 merely disclose VL or light chain CDRs (LCDR1, 2,3) without disclosing sequence or structure information regarding the corresponding cognate Hc which is required to form an antibody that binds to Claudin 18.2;
In contrast yet similar to these claims, claims 16, 19-23 merely disclose heavy chain variable (VH) region or heavy chain CDRs (HCDR1, 2,3) without disclosing sequence or structure information regarding the corresponding cognate light chain which is required to form an antibody that binds to Claudin 18.2.
Regarding claims that allow mix and exchange of antibody Lc or Hc CDRs or Lc/Hc pairs: claims 7, 16, 27:
Claims 7 allows mixing and exchange of the antibody light chain CDRs (LCDR1, 2, 3) outside of the LCDRs bearing the following 2 sets of LCDR 1, 2, 3 sequences with SEQ ID NO: 17-18-19 and SEQ ID NO: 23-24-19 present in MAb1-5 that possess the recited function of binding to Claudin 18.2. The specification does not provide information that supports the functionality of a new genus of antibodies covered by the claim.
Claim 16 allows heavy chain CDR (HCDR1, 2, 3) mixing and exchange outside of the tested HCDRs bearing the following 4 sets of HCDR1, 2, 3 sequences with SEQ ID NO: 20-21-22, SEQ ID NO: 25-26-27, SEQ ID NO: 28-29-30, and SEQ ID NO: 31-32-33, which are present in MAb1-5. The specification does not provide information that supports the functionality of a new genus of antibodies covered by the claim.
Claim 27 allows LCDR and HCDR mixing and exchange outside of the tested LCDR and HCDR sets as discussed above, and further allow random pairing of recited LCDRs and HCDRs. The specification does not provide information that supports the functionality of a new genus of antibodies covered by the claim.
Regarding claims that allow antibody sequence variations without specifying the location or identity of these variations: claims 10-12, 19-21, 29:
Claim 10 recites the VL region of the antibody or antigen binding fragment having amino acid sequences that has at least 95% sequence identity to that of SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, or SEQ ID NO: 13. As such, the claim is drawn to a genus of antibodies with the function of being an anti-Claudin 18.2 antibody which the specification does not support.
Claim 11 is drawn to a VL region of the antibody or antigen binding fragment having the recited amino acid sequences or any variant thereof having 1-10 substitutions, deletions, or insertions. As such, this claim is drawn to genus of antibodies with the function of being an anti-Claudin 18.2 antibody which the specification does not support.
Claim 12 is drawn to a VL region of the antibody or antigen binding fragment having the recited amino acid sequences, or any variant thereof having 1-10 conservative substitutions. As such, this claim is drawn to genus of antibodies with the function of being an anti-Claudin 18.2 antibody which the specification does not support.
Claim 19 recites the VH region of the antibody or antigen binding fragment having amino acid sequences that has at least 95% sequence identity to that of SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, or SEQ ID NO: 12. As such, the claim is drawn to a genus of antibodies with the function of being an anti-Claudin 18.2 antibody which the specification does not support.
Claim 20 is drawn to a VH region of the antibody or antigen binding fragment having the recited amino acid sequences or any variant thereof having 1-10 substitutions, deletions, or insertions. As such, this claim is drawn to genus of antibodies with the function of being an anti-Claudin 18.2 antibody which the specification does not support.
Claim 21 is drawn to a VH region of the antibody or antigen binding fragment having the recited amino acid sequences, or any variant thereof having 1-10 conservative substitutions. As such, this claim is drawn to genus of antibodies with the function of being an anti-Claudin 18.2 antibody which the specification does not support.
Claim 29 recites antibody or antigen binding fragment in claim 27, comprising 5 VL/VH pairs and their variants:
VL with a sequence of SEQ ID NO: 5, or a variant thereof; and VH with a sequence of SEQ ID NO: 4, or a variant thereof;
VL with a sequence of SEQ ID NO: 7, or a variant thereof; and VH with a sequence of SEQ ID NO: 6, or a variant thereof;
VL with a sequence of SEQ ID NO: 9, or a variant thereof; and VH with a sequence of SEQ ID NO: 8, or a variant thereof;
VL with a sequence of SEQ ID NO: 11, or a variant thereof; and VH with a sequence of SEQ ID NO: 10, or a variant thereof;
VL with a sequence of SEQ ID NO: 13, or a variant thereof; and VH with a sequence of SEQ ID NO: 12, or a variant thereof;
“a variant antibody or antigen binding fragment” is defined as those that retains at least 10% of its Claudin 18.2 binding activity when compared it parental antibody in the specification of the instant case. However, the specification does not provide information regarding the sequence or structure of these possible variants. As such, this claim is drawn to a genus of antibodies with the function of being an anti-Claudin 18.2 antibody which the specification does not support.
Regarding claims drawn to antibodies binding to specific residues in Claudin 18.2, claims 44 and 45:
Claims 44 and 45 are drawn to the antibody, or antigen binding fragment thereof, of claim 1 that binds to residues E56, N153, Y155, M158, and G159 of the Claudin 18.2 protein or residues V40, E56, N153, Y155, M158, G159, and G160 of the Claudin 18.2 protein, respectively. The specification of the instant case teaches a single antibody, MAb1, that binds to the residue groups in claim 44, and a single antibody, MAb2, that binds to the residue groups in claim 45. In both cases, a single antibody does not represent the whole genus of antibodies that can bind to the claimed residue groups. Therefore, the specification of the instant case does not provide adequate description to support the scope of these claims.
Regarding claims reciting antibody sequence in the form of “an amino acid sequence”: claims 7, 10-14, 16, 19-23, 27, 29
Claims 7, 10-14, 16, 19-23, 27, 29 recite “an” amino acid sequence as set forth in the recited sequences. For example, claim 7 recites “the LCDR1 has an amino acid sequence SEQ ID NO: 17 or SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19.” In the broadest reasonable interpretation of the claim, “an” amino acid encompasses segments or portions of the recited sequences rather than the entire sequence. Therefore, these claims establish genera that are not supported by the specification of the instant case.
Regarding claims 27 and 29 that claim an antibody with a set of HCDRs of SED ID NO:31-32-33 or a VH region bearing a set of HCDRs of SED ID NO:31-32-33, which is not demonstrated to perform the function of binding to Claudin 18.2.
State of the Relevant Art
Regarding scenarios 1), 2), 3) and 5) and 6), it is well established in the art that the formation of an intact antigen-binding site of a given antibody requires the association of the complete heavy and light chain variable regions, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations 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 (Janeway et al 2022, Chapter 4).
It is also well known that compatible pairing of heavy chain (Hc) and light chain (Lc) that allows generation of a functional and stable antibody is achieved in vivo through random combinatorial gene rearrangement, followed by stringent selection processes in the bone marrow, where only B cells producing well-paired, stable H-L chains survive (Janeway et al, Chapter 8). In contrast, when developing therapeutic antibodies ex vivo, identifying cognate pairs is a significant challenge. Therefore, it is known in the art that not every heavy-light combination forms a stable or functional antibody and to distinguish cognate from random H–L pairs is not an easy task.
Regarding antibody sequence variabilities in scenarios 2) and 3), it is known in the art that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al, see entire document, particularly the abstract and the middle of the left column of page 1982). More recently, Rabia et al (2018) “Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility” Biochem Eng. J. 15(137); 365-374 discusses the challenges with optimizing antibody properties and states that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity… antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs – especially the long and highly variable heavy chain CDR3 – to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 – page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations or alterations in the antibody structure, particularly in the CDR regions, is not a predictable task and requires experimentation following mutation to ensure that the binding affinity is maintained and a specific, stable antibody is created. These teachings demonstrate that a modification to even one amino acid of an antibody, particularly in the CDRs, would likely result in an antibody that is not suitable for binding as recited in the instant claims.
Regarding conservative substitutions of amino acid residues in antibody sequence, Lees et al. "Investigating substitutions in antibody–antigen complexes using molecular dynamics: a case study with broad-spectrum, influenza A antibodies." Frontiers in Immunology 8 (2017): 143 discusses a study on the impact of single amino acid substitutions on antibody-antigen binding energy using three broad-spectrum antibodies to influenza A hemagglutinin and find that in some cases the impact of a substitution is local, while in others it causes a reorientation of the antibody with wide-ranging impact on residue–residue interactions: this explains, in part, why the change in chemical properties of a residue can be, on its own, a poor predictor of overall change in binding energy (page 1, Abstract). Through AA substitutions in HA epitope and paratope in the three antibodies, Lees et al recites, “predictions made on the basis of chemical properties or straightforward inferences of critical residues may not be reliable.”
The specification of the instant case lists exemplary conservative amino acid substitutions in Table 1 (page 8, paragraph [0083]). Based on broadest reasonable interpretation, conservative substitution replaces an amino acid with another that has similar physicochemical properties such as size, charge or hydrophobicity. However, based on the importance of the CDR sequences in the variable region of an antibody taught by Rudikoff et al and Rabia et al, and the teaching of Lees et al which suggests that chemical similarity between residues should not be taken to imply sequence or structural invariance, which is critical to antibody function. The instant application fails to provide sufficient description regarding antibody sequence variations in claims 10-12, 19-21 such that a person with ordinary skills in the art would be able to discern a structure/function correlation for the antibodies with the claimed variations.
Regarding scenario 4), claims 44 and 45 claim antibody or antigen binding fragment that binds to residues E56, N153, Y155, M158, and G159 of Claudin 18.2 or residues V40, E56, N153, Y155, M158, G159, and G160 of Claudin 18.2, respectively, these claims recite functional limitations and claim a genus of antibodies by what they do (function), rather than by what they are (structure).
MPEP 2173.05(g) teaches that “Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C. 112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197.”
In this case, the antibodies claimed are based on the epitope to which they bind, not the structure of the antibodies that would result in the claimed functions.
The prior art also does not provide a representative number of species of antibodies having the claimed function nor does the prior art provide a structure-function correlation that could be used to identify such antibodies. Rather, the teaching of the prior art demonstrate that epitope binding is not predictable.
For instance, Hummer et al (2022) “Advances in computational structure-based antibody design” Current Opinion in Structural Biology 74(102379); 1-7 teaches that the traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (page 1, right column, paragraph 2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (page 1, right column, paragraph 3), demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating that “Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (page 4, right column, paragraph 3).
Hummer’s teaching regarding the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrates a lack of predictability in the field between antibody structure and function.
Regarding scenario 6), claims 27 and 29 claim Claudin 18.2 antibodies bearing 4 specific HCDRs/LCDRs pairs (claim 27) with disclosed sequences or 5 specific VH/VL pairs (claim 29) containing with corresponding HCDRs/LCDRs sets in claim 27. The specification of the instant case recited 5 antibodies: MAb1, MAb2, MAb3, MAb4, MAb5, with corresponding HCDR/LCDR sequences listed in a table on page 32, pargraph [00119] and corresponding VH/VL sequences listed in a table on page111, paragraph [00450]. The instant disclosure recites that MAb1, MAb2 and MAb3 are generated from immunizing chicken with VLPs displaying Claudin 18.2 protein and subsequent screening of scFv phage display library constructed from B cells of the immunized chicken. The instant disclosure demonstrated specific binding of MAb1, MAb2 and MAb3 to Claudin 18.2 (paragraphs [00569-00574], Fig. 1-4 and 6) and illustrated epitope matching strategy and the resultant epitopes (paragraph [00575-00577], Fig. 5) using Zolbetuximab as a clinical bench mark antibody in these characterizations. Based on sequence search using disclosed HCDR and LCDR sets, MAb1, MAb2, MAb3 bear novel HCDR sequences, MAb4 shares identical HCDRs and LCDRs with MAb3 with different FWR in the HCDRs, therefore is considered a functional variant of MAb3.
However, MAb5, which bears an LCDRs of SEQ ID NO: 23-24-19, shared by MAb1 and MAb5, bears a new set of HCDRs with sequences of SED ID NO:31-32-33 (contained in VH region of MAb5, SEQ ID NO.12). Although the sequence of MAb5 HCDRs are similar to MAb1 HCDRs (SED ID NO:28-29-30), sequence alignment (HCDR1, 2, 3 are separated by *) shows multiple mismatch amino acids in HCDR1, 2 and 3 between MAb1 and MAb5:
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Given the importance of CDR residues in forming the antigen binding site as discussed above and the fact that the disclosure provided no evidence of MAb5 binding to Claudin 18.2, an artisan would not be able to predict whether an antibody with this new set of HCDRs with mismatches in CDR1, CDR2 and CDR3 would bind specifically to Claudin 18.2 like MAb1, although MAb5 and MAb1 share sequence homology.
Overall, it is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of antibodies that are encompassed by the scenarios discussed above which involve claims 7, 10-14, 16, 19-23, 27, 29, 44-45. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable substitution of amino acids in the claimed sequences while maintaining binding function. Therefore, the instant claims were found to not meet the written description requirement.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 5-6, 46-49, 53-54 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sahin et al, “Combination therapy involving antibodies against claudin 18.2 for treatment of cancer” (US 2016/0339101A1, published Nov. 24, 2014).
Claim 1 is drawn to a recombinant antibody or antigen binding fragment that binds to claudin 18.2 protein in its native conformation. Claim 5 and 6 recite that the antibody or antigen binding fragment is a monoclonal antibody or a scFv antibody, respectively.
Sahin et al (2014) teach “an antibody having the ability of binding to CLDN18.2 binds to native epitopes of CLDN18.2 present on the surface of living cells.” (page 15, column 1, paragraph [089], and that the term "antibody" includes monoclonal antibodies and fragments or derivatives of antibodies, including single chain antibodies, e.g. scFv's and antigen binding antibody fragments such as Fab and Fab' fragments and also includes all recombinant forms of antibodies” (page 11, column 2, paragraph [0157].
Regarding claims 46-49, Sahin et al (2014) teach that “antibody genes can be ligated into an expression vector such as a eukaryotic expression plasmid (a nucleic acid molecule) well known in the art” and that “The purified plasmid with the cloned antibody genes can be introduced in eukaryotic host cells such as CHO cells, NS/0 cells, HEK293T cells or HEK293 cells or alternatively other eukaryotic cells like plant derived cells, fungal or yeast cells” (page 20-21, paragraph [0247]).
Regarding claim 49 which is drawn to a pharmaceutical composition comprising the antibody or antigen binding fragment in claim 1, Sahin et al (2014) teach in “preclinical studies” wherein the in vivo anti-tumor effect of Claudin 18.2 antibodies was tested by administering the antibodies into mice (page 23, paragraph [0263-0264]) and such agent “may be administered in the form of any suitable pharmaceutical composition” (page 23, column 1, paragraph [0266]).
Regarding claims 53-54 which are drawn to a method of treating a tumor with the antibody or antigen binding fragment in claim 1 and the type of tumors in a subject, Sahin et al (2014) teach “A method of treating or preventing a cancer disease characterized by cells expressing claudin 18 splice variant 2, comprising administering to a patient an antibody having the ability of binding to claudin 18 splice variant 2 (CLDN 18.2) in combination with an agent stabilizing or increasing expression of CLDN 18.2” (page 60, claim 1), and that “the cancer disease is selected from the group consisting of esophageal adenocarcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, cancer of the stomach, cancer of the esophagus, in particular the lower esophagus, gastric cancer, cancer of the eso-gastric junction and gastroesophageal cancer” (page 60, claim 12), which meet the limitations in claims 53 and 54.
Claims 1, 41-42 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sahin et al, “Bispecific trivalent antibodies binding to Claudin 6 or Claudin 18.2 and CD3 for treatment of claudin expressing cancer diseases” (US 2019/0309067 A1, published October, 2019).
Claim 41 recites that the antibody or antigen binding fragment of claim 1 additionally comprise at least one additional peptide that binds to a different target antigen, and claim 42 recites that this different antigen can be CD3 or CD28.
Sahin et al (2019) teach a binding agent comprising at least three binding domains, wherein a first binding domain binds to a T cell-specific antigen and a second binding domain and a third binding domain bind to a claudin” in claim 1 (page 126). Sahin et al (2019) name this binding agent “bispecific chimeric TriMAB” (bstb) which has an antigen binding fragments (Fab) specific for the human T cell receptor component, CD3e and two single chain variable fragments (scFv) specific for the human tumor associated antigen CLDN18.2 (Claudin 18.2). Sahin et al further recites that the corresponding VH and VL of the CLDN18.2 scFv are derived from the chimeric IgG1 antibody, IMAB32, originally developed by Ganymed Pharmaceuticals AG, as evidenced by Woll et al (2014). (page 42, Example 8, paragraph [0533]m, Figure 10B). Therefore, these teachings anticipate limitations in claims 41-42.
Conclusion
All claims are rejected.
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/HONG REN/
Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647