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 .
Priority
The instant application, filed on 11/07/2022, claims priority to the US Provisional application 63/278,999 filed on 11/12/2021. The instant application will be examined with an effective filing date of 11/12/2021.
Status of the Claims/Application
Claims 3, 5, 7, 9, 11-12, 15, 17, 25-41, 43-116, and 120-125 are canceled. Claims 1-2, 4, 6, 8, 10, 13-14, 16, 18-24, 42 and 117-119 are currently pending and are herein under examination on the merits.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 02/09/2023 and 05/12/2023 are acknowledged and are in compliance with the provisions of CFR 1.97. They have been considered by the examiner.
Response to Election/Restrictions
Applicant remarks filed on 12/18/2025 in regards to election of species submitted on 10/22/2025 is acknowledged and enter herein on the merits.
For Species 1, Applicant elects SEQ ID NOS: 27, 28, and 29 for vhCDR1-3 and SEQ ID NOS: 30, 31, and 32 for vlCDR1-3 of 38E2[B7H3]_H2_L1.1, which are the 6 sequences of hvCDR1-3 and lvCDR1-3 for the B7H3 antigen binding domain of 38E2[B7H3]_H2_L1.1.
For Species 2, Applicant elects SEQ ID NOS: 2612-2614 for vhCDR1-3 and SEQ ID NOS: 26 16- 2618 for vlCDR1-3 of mAb-D[NKG2D], which are the 6 sequences of hvCDR1-3 and lvCDR1- 3 for the NKG2D antigen binding domain of mAb-D[NKG2D].
Claim Rejections - 35 USC § 112
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 2, 4, 14, 19 and 42 are rejected because the claims recite references to Figures 13 and 14, 23 and 58, 1A-1E, 19 and 59, and 19 and 59 respectively. See MPEP 2173.05(s).
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.
Claims 1, 6, 10, 13, 20-23 and 117 are rejected under 35 U.S.C. 103 as being unpatentable over US 2021/0206859 A1, and further in view of Lazar et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad. Sci U S A. 2006 Mar 14;103(11):4005-10, herein further referred to as Chang and Lazar respectively.
Regarding claim 1, Chang teaches a protein (heterodimeric antibody) comprising:
A first monomer comprising
i) an anti-NKG2D scFv (Chang para 0032) comprising a first variable heavy VH1 domain, an scFv linker and a first variable light VL1 domain (Chang Fig. 2A) and
ii) a first Fc domain (Chang Fig. 2A), wherein the scFv is covalently attached to the N-terminus of the first Fc domain using the domain linker (Chang para 0176),
a second monomer comprising a VH2-CH1-hinge-CH2-CH3 monomer, wherein VH2 is a second variable heavy domain and CH2-CH3 is a second Fc domain; and (Chang para 0171 and Fig. 2A)
a light chain comprising a second variable light VL2 domain,
wherein the second variable heavy VH2 domain and the second variable light VL2 domain for an B7H3 antigen binding domain (Chang para 0032 and Fig. 2A), and
wherein the first Fc domain and/or the second Fc domain comprises an amino acid substitutions according to the EU numbering at the FcγRIIIA (CD16a) binding site so as to enhance or reduce the binding affinity to CD16 compared to the first and second Fc domains lacking the substitution(s) (Chang para 0200).
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Chang does not specifically teach of amino acid substitutions as claimed in the instant claim.
Lazar teaches single double and triple engineered Fc variants with amino acid substitutions at S239D, I332E, S239D/I332E and S239D/I332E/A330L according to EU numbering (Lazar pg. 4005 col 2 para 4 and Fig. 1A) all had increase in binding affinity to FcγRIIIa and thereby an increase in effector function, enable efficacy against cell expressing low levels of target antigen and result in increased cytotoxicity in an in vivo preclinical model (Lazar Abstract).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Chang in view of Lazar with a reasonable high degree of predictable success so as to design a heterodimeric antibody as described by Chang and having amino acid substitutions as indicated by Lazar in the hinge region to improve the binding affinity of the antibody to FcγRIIIa so as to improve its effector function, enable efficacy against cell expressing low levels of target antigen and result in increased cytotoxicity in an in vivo preclinical model. Therefore, a skilled artisan would have been motivated to design an antibody as described above for the use in the treatment of cancer wherein the antibody has the ability to bind a site such as B7H3 on a cancer cell and NKG2D receptor and CD16 on natural killer cells to activate the natural killer cells (Chang para 0024).
Regarding claim 6, and incorporating the analysis of claim 1 above, Chang teaches that the anti-NKG2D scFv can be fused to the N-terminus of the constant region CH2 domain via a linker sequence (Chang para 0176).
Regarding claims 10 and 13, and incorporating the analysis of claim 1 above, Chang does not specifically teach amino acid substitutions in the first or second domain wherein the substitution is S239D/I332E.
Lazar teaches that an antibody variant having a substitution S239D/I332E showed substantial ADCC enhancement than wild type trastuzumab across a broad range of antigen expression levels (Lazar pg. 4007 col 1 para 2 and Fig. 4).
Therefore, it would have been obvious before the effective filing date for a skill artisan to modify the teachings of Chang in view of Lazar with a reasonable high degree of predictable success to use the amino acid substitution S239D/I332E on either the first or second domain so as to enhance the ADCC across a range of antigen expression levels. Therefore, a skilled artisan would have been able to design the first or second domain with amino acid substitutions S239D/I332E as indicated by Lazar.
Regarding claims 20-23, and incorporating the analysis of claim 1 above, Chang teaches that the antibody described can made suing recombinant DNA technology by skilled person in the art wherein the first nucleic acid sequence encoding the first Fc domain can be cloned into a first expression vector and the second nucleic acid sequence encoding the second Fc region can be cloned into a second expression vector first and second expression vectors can be stably transfected together into a host cell to produce the heterodimeric antibody (Chang para 0254). Change further teaches that the clones can be cultured under conditions suitable for bio-reactor scale-up and maintained expression of the heterodimeric antibody (Chang para 0256).
Regarding claim 117, and incorporating the analysis of claim 1 above, Chang teaches that the multi-specific antibody as described above can be used for treating cancer by administering to the subject a therapeutically effective amount of the multi-specific antibody (Chang Abstract and para 0107).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Chang and Lazar as applied to claim 1, and further in view of US11919958B2, herein further referred to as Desjarlais.
Regarding claim 2, and incorporating the analysis of claim 1 above, Chang and Lazar does not teach of the SEQ ID NO: 27-29 for vhCDR1-3 and SEQ ID NOs: 30-31 for vlCDR1-3 as claimed in the instant claim.
Desjarlais teaches a sequence with SEQ ID NO: 973-975 for vhCDR1-3 and SEQ ID NO: 977-979 for vlCDR1-3 as exemplary B7H3 binding domain (Desjarlais col 29 ln 14-26 and Fig. 31).
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Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings to Chang and Lazar in view of Desjarlais with a reasonable degree of predictable success to use SEQ ID NOs: 973-975 for vhCDR1-3 and SEQ ID NOs: 977-979 for vlCDR1-3 in place of the sequences used by Chang for the B7H3 binding domain so as to obtain the heterodimeric antibody as claimed.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Chang and Lazar as applied to claim 1, and further in view of US 7879985B2, herein further referred to as Urso.
Regarding claim 4, and incorporating the analysis of claim 1 above, Chang and Lazar do not specifically teaches of amino acid sequences of the vhCDR1-3 and vlCDR1-3 as claimed.
Urso teaches that vhCDR1-3 and vlCDR1-3 have amino acid sequences as below, wherein SEQ ID NOS: 2612-2614 is SEQ ID NO: 70 and SEQ ID NOS: 2616-2618 is SEQ ID NO: 71 of the instant applicant and Urso respectively. Urso further teaches that anti-hNKG2D can be prepared as a single-chain Fv for use in the design of antibodies (Urso col 24 ln 44-50).
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SEQ ID NOS: 2612-2614 is SEQ ID NO: 70
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SEQ ID NOS: 2616-2618 is SEQ ID NO: 71.
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Chang and Lazar in view of Urso with a reasonable high degree of predictable success to use the sequences of Ursa for the design of anti-NKD2G as an scFv as indicated by Ursa.
Claims 8, 14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Chang and Lazar as applied to claim 1, and further in view of Moore et al. A robust heterodimeric Fc platform engineered for efficient development of bispecific antibodies of multiple formats. Methods (San Diego, Calif.). 2019 Feb;154:38-50, herein further referred to as Moore.
Regarding claim 8, and incorporating the analysis of claim 1 above, Chang and Lazar do not teach of a charged scFv linker.
Moore teaches an exemplary heterodimer the used an scFv pI-increasing linker (GKPGS)4 between the VH and VL and placed it on the high (E357Q/S364K ) pI Fc chain to further increase the differences in the pI among the heterodimer and its related side product during ion exchange chromatography (IEX) (Moore pg. 45 col 2 para 2). Moore further teaches that their approach for design of heterodimer by incorporating electrostatic component into their design provided synergy with pI -engineered Fc region allows industry standard IEX purification of the heterodimer species (Moore pg. 48 col 2 para 2)
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Chang and Lazar in view of Moore with a reasonable high degree of predictable success so as to use a charged scFv linker as suggested by Moore for the design of the anti-NKG2D scFv wherein the charged linker will change the pI of the heterodimeric antibody thereby beneficial for its purification or during IEX characterization. Therefore, a skilled artisan would have been able to modify the teachings of Chang and Lazar in view of Moore to use a charge scFv linker in the design of the anti-NKG2D scFv.
Regarding claims 14 and 16, and incorporating the analysis of claim 1 above, Chang and Lazar do not specifically teach of a set of heterodimerization variants for the first and second Fc domains as listed in Fig. 1A-1E according to EU numbering.
Moore teaches of a first and second Fc domains set of heterodimerization variant comprising L368D/K370S and E357Q/S364K (Fig. 1B of applicant’s Drawings submitted on 11/07/2022) on the first and second Fc domains respectively that was more stable than the wild type IgG4 (Moore pg. 48 col 2 para 2). Moore also shows that the L368D/K370S and E357Q/S364K set has a yield of 95.1% compared to other sets (Moore Tab. 2).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Chang and Lazar in view of Moore with a reasonable degree of predictable success to design the first and second Fc domains with a heterodimerization set L368D/K370S and E357Q/S364K for the first and second Fc domains respectively so as to obtain a more stable variant and improve the yield of the antibody as suggested by Moore. Therefore, a skilled artisan would have been able to follow the suggestions of Chang and Lazar in view of Moore to design the antibody as claimed.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Chang and Lazar as applied to claim 1, and further in view of Suzuki et al. The influence of antibody engineering on Fc conformation and Fc receptor binding properties: Analysis of FcRn-binding engineered antibodies and an Fc fusion protein. MAbs. 2021 Jan-Dec;13(1), herein further referred to as Moore.
Regarding claim 18, and incorporating the analysis of claim 1 above, Chang and Lazar do not teach a heterodimeric antibody with amino acid substitutions selected from M428L/N434S, M428L/N434A and M252Y/S254T/T256E according to EU numbering on either the first or second Fc domain.
Suzuki teaches two amino acid substitutions M428L/N434A in the Fc region wherein the substitutions can modulate its affinity to FcRn (Suzuki pg. 1 col 1 para 2). Suzuki further teaches two therapeutic antibodies that are in clinical trials (MEDI8897 and MEDI4893) that have substitutions M252Y/S254T/T256E (Suzuki pg. 1 col 2 para 2 and Fig. 1) so as to modulate their binding to FcRn in order to improve the half-life of the antibody wherein the antibody variant with amino acid substitution(s) have a better have-life than the antibody without the substitution (Suzuki Abstract).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Chang and Lazar in view Suzuki with a reasonable high degree of predictable success to engineer the first or second Fc domain with substitutions such as M428L/N434A, M252Y/S254T/T256E to modulate the binding of the antibody to it FcRn.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over US 2021/0206859 A1, and further in view of Lazar et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4005-10, herein further referred to as Chang and Lazar respectively.
Regarding claim 24, Chang teaches a protein (heterodimeric antibody) comprising:
A first monomer comprising
i) an anti-BH73 scFv (Chang para 0033) comprising a first variable heavy VH1 domain, an scFv linker and a first variable light VL1 domain (Chang Fig. 2B) and
ii) a first Fc domain (Chang Fig. 2B), wherein the scFv is covalently attached to the N-terminus of the first Fc domain using the domain linker (Chang para 0176)
a second monomer comprising a VH2-CH1-hinge-CH2-CH3 monomer, wherein VH2 is a second variable heavy domain and CH2-CH3 is a second Fc domain; and (Chang Fig. 2B)
a light chain comprising a second variable light VL2 domain,
wherein the second variable heavy VH2 domain and the second variable light VL2 domain for an B7H3 antigen binding domain (Chang para 0033 and Fig. 2B), and
wherein the first Fc domain and/or the second Fc domain comprises an amino acid substitution according to the EU numbering at the FcγRIIIA (CD16a) binding site so as to enhance or reduce the binding affinity to CD16 compared to the first and second Fc domains lacking the substitution(s) (Chang para 0200).
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Chang does not specifically teach of amino acid substitutions as claimed in the instant claim.
Lazar teaches single double and triple engineered Fc variants with amino acid substitutions at S239D, I332E, S239D/I332E and S239D/I332E/A330L according to EU numbering (Lazar pg. 4005 col 2 para 4 and Fig. 1A) all had increase in binding affinity to FcγRIIIa and thereby an increase in effector function, enable efficacy against cell expressing low levels of target antigen and result in increased cytotoxicity in an in vivo preclinical model (Lazar Abstract).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Chang in view of Lazar with a reasonable high degree of predictable success so as to design a heterodimeric antibody as described by Chang and having amino acid substitutions as indicated by Lazar in the hinge region to improve the binding affinity of the antibody to FcγRIIIa so as to improve its effector function, enable efficacy against cell expressing low levels of target antigen and result in increased cytotoxicity in an in vivo preclinical model. Therefore, a skilled artisan would have been motivated to design an antibody as described above for the use in the treatment of cancer wherein the antibody has the ability to bind a site such as B7H3 on a cancer cell and NKG2D receptor and CD16 on natural killer cells to activate the natural killer cells (Chang para 0024).
Claim 118 is rejected under 35 U.S.C. 103 as being unpatentable over Chang and Lazar as applied to claims 1 and 117 above, and further in view of Hu et al. Discovery of a novel IL-15 based protein with improved developability and efficacy for cancer immunotherapy. Sci Rep 8, 7675 (2018), herein further referred to as Hu.
Regarding claim 118, and incorporating the analysis of claims 1 and 117 above, Chang teaches that the multi-specific antibody as described above can be co administered with additional therapeutics agents to treat cancer (Chang para 0297), wherein the agents can be IL-2 and/or IL-15 (Chang para 0301).
Chang or Lazar do not teach of an IL-12-Fc fusion or IL-15-Fc fusion protein.
Hu teaches an IL-15 fc fusion protein (P22339) that has improved developability and efficacy for cancer immunotherapy than naturally occurring IL-15. Hu also teaches that while naturally occurring IL-15 can promote both innate and adaptive immune reactions by stimulating CD8+/CD4+ T cells and natural killer cells (NK) while showing no effect in activating T-regulatory (Treg) cells or inducing activation-associated death among effector T cells and NK cells. Hu further teaches that P22339 improves this shortcoming and demonstrates excellent developability, pharmacokinetic and pharmacodynamic properties as well as antitumor efficacy in both in vitro assessments and in vivo studies. It significantly suppresses tumor growth and metastasis in rodent models, and activates T effector cells and NK cells in cynomolgus monkey (Hu Abstract). Hu also teaches that half-life of IL-15 is improved when it is fused to the Fc domain as in the case for P22339 (Hu Abstract)
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Chang and Lazar in view of Hu with a reasonable high degree of predictable success to co-administer use the P22339 of Hu instead of the IL-15 as indicated by Chang (Para 0301) where P22339 will better enhance the activation of NK cells and antitumor activity and improve the half-life of the IL-15 during therapy. Therefore, a skilled artisan would have been able to co-administer the heterodimeric antibody with an IL-15 Fc fusion protein such as P22339 so as to improve the activation of NK cells as compared to using the naturally occurring IL-15 as in the method of Chang.
Claim 119 is rejected under 35 U.S.C. 103 as being unpatentable over Chang and Lazar as applied to claims 1 and 117 above, and further in view of Skokos et al. A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies.Sci. Transl. Med.12,eaaw7888(2020) and Serrano-Pertierra et al. NKG2D- and CD28-mediated costimulation regulate CD8+ T cell chemotaxis through different mechanisms: the role of Cdc42/N-WASp. J Leukoc Biol. 2014 Mar;95(3):487-95, herein further referred to as Skokos and Serrano-Pertierra respectively.
Regarding claim 119, and incorporating the analysis of claims 1 and 117 above, Chang teaches that the multi-specific antibody as described above can be co administered with additional therapeutics agents to treat cancer (Chang para 0297).
Chang and Lazar does not specially teach that the coadministration of the heterodimeric antibody with a bispecific T cell engager.
Skokos teaches the co administrations of CD28-bispecific and CD3-bispecific antibodies so as to enhance the antitumor activity of the CD3-bispecific antibodies. Skokos further teaches that tumor-specific antigen (TSA)-CD28 bispecific antibodies showed limited activity and no toxicity when used alone, but when combined with TSAxCD3 bispecific antibodies, they enhanced the artificial synapse between a T cell and its target cell, potentiate T cell activation and markedly improve antitumor activity of CD3 bispecific antibodies, and that combining CD28-costimulatory bispecific antibodies with TSAxCD3 bispecific may provide well-tolerated, off-the-shelf antibody therapies with robust antitumor efficacy (Skokos Abstract and pg. 8 col 2 para 2-4).
Serrano-Pertierra teaches NKG2D and CD28 mediate CD8+ T cells chemotaxis but through different mechanism and that both NKG2D and CD28 impairs cell migration. Serrano-Pertierra also teach that while the Rho GTPase Rac1 is activated upon TCR and costimulation via CD28 and NKG2D, the activity of Cdc42 is increased only upon CD3/NKG2D activation.
Therefore it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Chang and Lazar in view of Skokos and Serrano-Pertierra with a reasonable high degree of predictable success to co-administer the heterodimeric antibody with a bispecific T cell engager (BiTe) wherein the combination therapy will result in the enhancement of the artificial synapse between the T cell and its target cell, potentiate T cell activation and improve antitumor activity of the BiTe and the heterodimeric antibody. As indicated by Serrano-Pertierra NKG2D and CD28 both mediate chemotaxis and cell migration although thorough different pathways. Therefore, a skilled artisan would have been able to co-administer the heterodimeric antibody with a BiTe that has a complementary stimulatory pathway for the stimulation to the T cells and/or enhance the artificial synapse between the T cell and its target so as to improve the antitumor activity of the antibodies.
Allowable Subject Matter
Claims 19 and 42 contain allowable subject matter.
The following is an examiner’s statement of reasons for allowance:
Due to the unpredictability nature of antibodies as demonstrated by Rudikoff et al., a single modification of an amino acid in the binding domain is capable of altering the antigen-binding specificity (Rudikoff pg. 4 col 1 2 and Abstract) of an antibody, therefore, the claimed sequences (SEQ ID NOS: 4-6, SEQ ID NOS: 1309-1310 and 6 and SEQ ID NOS: 1313-1314 and 6) for the anti-NKG2D scFv/anti-B7H3 Fab antibody of instant claim 19 and of anti-NKG2D Fab/anti-B7H3 scFv construct (SEQ ID NO: 1, 2,and 3 of XENP38597, SEQ ID NOS: 7, 8 and 3 of XENP38101, SEQ ID NOS: 9, 10 and 3 of XENP38108 and SEQ ID NOS: 12, 2 and 13 of XENP38598) of instant claim 42 are deemed free of the art.
The prior art neither suggest or teaches the claimed anti-NKG2D/B7H3 antibodies, defined by the claimed sequences in instant claims 19 and 42. The closest prior art is Chang.
Although Chang teaches an anti-NKG2D/B7H3 antibody, Chang does not teach the anti-NKG2D/B7H3 antibody having the novel amino acid sequences present in the instant application’s claims 19 and 49. While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since a skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions and deletions in the antigen binding domains. Chang’s teaches amino acid sequences, Chang’s SEQ ID NO: 214 has a locality match of 47.5% to instant SEQ ID NOS: 1314.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMMANUEL LED YOUTCHOM PENDIE whose telephone number is (571)272-6313. The examiner can normally be reached Mon - Fri: 8AM - 5PM CST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanna Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMMANUEL LED YOUTCHOM PENDIE/ Examiner, Art Unit 1647
/JOANNE HAMA/ Supervisory Patent Examiner, Art Unit 1647