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 .
Applicant’s amendments have overcome the objections to the specification, the claims, the rejection under 35 USC §112(a), and most of the rejections under 35 § USC 112(b).
It is noted that newly presented SEQ ID NOs: 36, 37, 39, 48, 49, and 53-56 have support in paragraphs [0433 and 0874].
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2, 4, 8, 11, 20, 22, 25, 27, 30, 33, 43, 44, 48, 56, and 58-60 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Instant claim 1 recites:
(Currently amended) An immunogenic composition comprising:
a first Pseudomonas aeruginosa filamentous (Pf) bacteriophage peptide, or derivative thereof, comprising an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NO: 3-8, 36. 38-44, or 56;
a second Pf bacteriophage peptide, or derivative thereof, comprising an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NO: 20-25, 37, 45-49, or 53-55; wherein the second Pf bacteriophage peptide, or derivative thereof, is different from the first Pf bacteriophage peptide or derivative thereof; and
one or more carriers wherein each carrier is CRM-197;
wherein the Pf bacteriophage peptides, or derivatives thereof, are independently coupled to the one or more carriers; and an adjuvant comprising a TLR4 agonist.
Claim 2, dependent from claim 1, requires a first conjugate comprising the first Pf bacteriophage peptide, or derivative,coupled to a first carrier; and
a second conjugate comprising the second Pf bacteriophage peptide, or derivative, coupled to a second carrier; or
(ii) an immunogenic conjugate comprising the first and second Pf bacteriophage peptides, or derivatives thereof, coupled to a first carrier.
However, claim 1 already requires a first and second Pf bacteriophage peptides independently coupled to one or more carriers. Claim 2 fails to further limit claim 1.
Claims 4, 8, 11, 20, 22, 25, 27, and 29 fail to further limit claim 1 because the attributes required by the sequences recited in claim 1, lines 2-4 possess: an 20-25% of acidic residues from the acidic region of the coat protein B (coaB) and are between 12-25 residues in length (required in instant claim 4); possess amino acid residue features required by formula (A), recited in claims 8, 11, 20, 22, 25, and 27, and are indistinguishable from the specific SEQ ID NOs: recited in claim 29. Claims 30, 33, 43, 44, and 47 fail to further limit claim 1 because the attributes required by the sequences recited in claim 1, lines 5-7 possess: amino acid residue features required by formula (B), recited in claims 30, 33, 43, and 44 and are indistinguishable from the specific SEQ ID NOs: recited in claim 47.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims complies with the statutory requirements.
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.
Claim 48 remains 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.
Lines 8-9 of claim 48 recites: “each linker-binding moiety is a cysteine and the thiol of the cysteine is bonded to the linker moiety”. This phrase appears to state that the linker-binding moiety is bonded to the linker moiety (itself) through the thiol of a cysteine? The meaning of this phrase cannot be determined.
Applicant provided no amendment to the claim and no explanation was provided to clarify the claim meaning. The rejection is maintained for reasons if record.
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 1-2, 4, 8, 11, 20, 22, 25, 27, 29-30, 33, 43-44, 47-48, 56, and 58-60 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.
Instant claim 1 requires a TL4 agonist as the adjuvant. The instant published disclosure identifies the following as TLR4 agonists: monophosphoryl lipid A (MPLA), glucopyranosyl lipid A (GLA), aminoalkyl glucosamide 4-phosphate (AGP), and Diamino allose phosphate (DAP). However, structures, compounds, or small molecule structures that function as TL4 agonists are not readily predictable or identifiable to the skilled artisan, as evidenced by Kadivella et al. (Communications Biology. 2025 Sep 29; 8 (1): 1382). Kadivella et al. screen a ZINC database to identify TLR4-targeting molecules and compared them to MPLA under identical conditions, see “Structure-based virtual screening of small-molecule TLR4 binding
compounds”. The inspiration to identify alternative TLR4 agonists to Monophosphoryl Lipid A (MPLA) and Glucopyranosyl Lipid A (GLA) by Kadivella et al. is due to MPLA’s heterogeneity, high cost, complex synthesis, and dose dependent toxicity. See the Introduction and Discussion sections. Of the top five compounds with similar binding energies to MPLA, only one, “NSF-951”, enhanced specific antibody and T-cell responses without observable toxicity, but future evaluations regarding the adjuvanticity and safety of NSF-951 formulated with various antigens and co-adjuvants, are required.
The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only TLR4 agonists identified are monophosphoryl lipid A (MPLA), glucopyranosyl lipid A (GLA), aminoalkyl glucosamide 4-phosphate (AGP), and Diamino allose phosphate (DAP). There is no disclosure of sufficient characteristics of the claimed genus of TLR4 agonists to allow persons of ordinary skill in the art to recognize that applicants were in possession of the claimed genus of TLR4 agonists. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. A definition by function alone is not sufficient because it is only an indication of what a thing does, rather than what it is. Eli Lily, 119 F.3 at 1568, 43 USPQ2d at 1406.
The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the distinguishing, identifying characteristics of the encompassed genus of TLR4 agonists claimed. The claims do not meet the written description provision of 35 U.S.C. 112, first paragraph.
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.
Claims 1, 2, 4, 8, 11, 20, 22, 25, 27, 29, 30, 33, 43, 44, 47, and 58-60 are rejected under 35 U.S.C. 103 as being unpatentable over Sweere et al. (Science. 2019; 363: 1416), Bollyky et al. (USPgPub 2017/0021020), the sequence alignment of instant SEQ ID NO: 20 with UniProt db access no A0A231ZXE0 by Freschi et al. Oct 25-2017, Seid et al. (WO 90/06696), Pichichero (Human vaccines & immunotherapeutics. 2013 Dec 24; 9 (12): 2505-2523), Masure et al. (US 6,245,335), Ogunniyi et al. (Infection and Immunity. 201; 69 (10): 5997-6003), and Román-Cruz et al. (The Journal of Immunology. 2020 May;204(1_Supplement):168). All references of record.
In the first two paragraphs under “Antibodies directed against Pf4 prevent Pseudomonas aeruginosa (Pa) colonization”, Sweere et al. identify a region of CoaB, the major coat protein of Pf phages, that is broadly conserved across 669 isolates of Pa (Fig. 7A). The Coab sequence of Sweere et al. is:
“GVIDTSAVESAITDGQGDMKAIGGYIVGALVILAVAGLIYSMLRKA”.
In “CoaB consensus sequence analysis” and Figure 7A, this sequence is conjugated to keyhole limpet hemocyanin (KLH), see Figure S14A. These teachings correspond to a first Pf phage peptide coupled to a first carrier protein, as required by instant claims 1, 2, and claim 4 (i-iii). In “CoaB peptide immunization protocol”, Sweere et al. teach the composition further comprises an adjuvant, as required by instant claim 58. Administration of the composition by Sweere et al induces humoral immunity and reduces the incidence of would infections by half, see In “Antibodies directed against Pf4 prevent Pseudomonas aeruginosa (Pa) colonization” and Figures S14B and 7B, as required by instant claims 59 and 60.
Sweere et al. do not teach a Pf phage peptide that is between 12-25 residues in length, as required by instant claims 4, 8, 11, 20, 22, 25, 27, and 29.
Bollyky et al. claim a vaccine comprising GVIDTSAVESAITDGQGDM (SEQ ID NO: 1), which is identical to instant SEQ ID NO: 3 recited in instant claim 29, and possesses all of the structural alternatives recited in instant claims 4, 8, 11, 20, 22, 25, and 27.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have coupled the peptide of Bollyky et al. to the KLH carrier protein of Sweere et al. because both peptides of Bollyky et al. and Sweere et al. possess the same 19 residues and both peptides are used to protect against Pf-family bacteriophage, see the first two paragraphs under “Antibodies directed against Pf4 prevent Pseudomonas aeruginosa (Pa) colonization” and Figures S14B and 7B of Sweere et al. and paragraphs [0087-0088] and claim 20 of Bollyky et al.
Neither Sweere et al. nor Bollyky et al. teach a second Pf bacteriophage peptide or conjugating a second Pf bacteriophage peptide to the same carrier protein, as required in instant claims 1 and 2. None of the references teach SEQ ID NO: 20, recited in instant claims 1 and 47, which includes all of the structural alternatives recited in instant claims 30, 33, 43, and 44.
The sequence of UniProt db access no A0A231ZXE0 by Freschi et al. shares 100% sequence identity with instant SEQ ID NO: 20, see the sequence alignment provided.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have incorporated the protein of Freschi et al. as the second peptide in the composition of Sweere et al. and Bollyky et al. because Freschi et al. identify the sequence as part of the major coat protein in line “DE” of the alignment. One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have included the peptide of Freschi et al. in the composition of Sweere et al. and Bollyky et al. to induce a broader immune response against multiple portions of the major coat protein. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have included the peptide of Freschi et al. in the composition of Sweere et al. and Bollyky et al. because the combined teachings of Sweere et al., Bollyky et al., and Freschi et al. teach two sequences of the major coat protein and it is routine in the vaccine art to administer more than one protein/peptide against a target, as evidenced by claims 1, 6, 10 and 11 of Seid et al., claims 1 and 9-19 of Masure et al.; and the abstract, Table 2 and Discussion of Ogunniyi et al.
Sweere et al. teach conjugating the Coab peptide to keyhole limpet hemocyanin (KLH). None of the references teach conjugating one or more peptides to be independently to CRM197, recited in claims 1 and 2.
Román-Cruz et al. teach conjugating a consensus Pf phage coat protein to CRM197, see the abstract provided.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have independently conjugated one or more Pf phage peptides of Sweere et al. and Freschi et al. to CRM197, as taught by Román-Cruz et al., to enhance humoral immunity to the Pf peptide, as taught by Román-Cruz et al.; in the first paragraph on page 68, Seid et al. teach conjugation of peptides to CRM197 does not alter the T cell recognition of the peptide, see Table 3; and Pichichero teach CRM197 is nontoxic, see the first two columns of “Characteristics of Carrier Proteins”. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have independently conjugated one or more Pf phage peptides of Sweere et al. and Freschi et al. to CRM197, as taught by Román-Cruz et al., because conjugating peptides to carrier protein CRM197 is routine in the art, as evidenced by Seid et al. (1990) and Pichichero teach CRM197 has a larger quantity of lysyl side-chains available for conjugation, see the first two columns of “Characteristics of Carrier Proteins”.
None of Sweere et al., Bollyky et al., Freschi et al., Seid et al., Pichichero, Masure et al. or Román-Cruz et al. teach an adjuvant comprising a TLR4 agonist, recited in instant claim 1 and one or more additional adjuvants, recited in instant claim 58.
In “Formulation of vaccine antigens”, Ogunniyi et al. teach co-administration of antigens in a mixture of (TLR4 agonist) monophosphoryl lipid A (MPL) and aluminum phosphate (AlPO4) adjuvants.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have administered the immunogenic composition of Sweere et al., Bollyky et al., Freschi et al., Seid et al., Pichichero, Masure et al. and Román-Cruz et al. with the monophosphoryl lipid A (MPL) and aluminum phosphate (AlPO4) adjuvants of Ogunniyi et al. to elicit high antibody titers and induce significantly longer survival times, see the abstract, Table 1, and Table 2 of Ogunniyi et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have administered the immunogenic composition of Sweere et al., Bollyky et al., Freschi et al., Seid et al., Pichichero, Masure et al. and Román-Cruz et al. with the monophosphoryl lipid A (MPL) and aluminum phosphate (AlPO4) adjuvants of Ogunniyi et al. because Román-Cruz et al. administer conjugated Pf peptides with plural adjuvants to enhance humoral and cell-mediated immunity, see the abstract provided.
Claim 48 is rejected under 35 U.S.C. 103 as being unpatentable over Sweere et al., Bollyky et al., Freschi et al., Seid et al., Masure et al., Ogunniyi et al., Pichichero, and Román-Cruz et al. as applied to claims 1, 2, 4, 8, 11, 20, 22, 25, 27, 29, 30, 33, 43, 44, 47, and 58-60 above, and further in view of Möginger et al. (Scientific reports. 2016 Feb 4; 6 (1): 20488), of record.
See the teachings of Sweere et al., Bollyky et al., Freschi et al., Seid et al., Ogunniyi et al., Pichichero, Masure et al. and Román-Cruz et al. above. None of the references teach or suggest the Pf bacteriophage peptide coupled to the carrier by a heterobifunctional linker, where the linker is attached at a terminal amino acid of the Pf peptide and attached to a lysine of the carrier. None of the references teach “each linker-binding moiety is a cysteine and the thiol of the cysteine is bonded to the linker moiety”, however, the intended meaning of this architecture cannot be determined.
Möginger et al. teach carrier protein CRM197 in vaccine conjugation requires a heterobifunctional linker, a lysine attachment residue to a carrier protein, and an amine group (terminal amino acid) attachment residue, see Figure 1. Though Möginger et al. do not depict the terminal amino acid of a Pf peptide, one of ordinary skill in the art prior to the instant effective filing date would have appreciated this feature because Román-Cruz et al. teach conjugating a consensus Pf phage coat protein to CRM197, see the abstract provided.
Claim 56 is rejected under 35 U.S.C. 103 as being unpatentable over Sweere et al., Bollyky et al., Freschi et al., Seid et al., Masure et al., Ogunniyi et al., Pichichero, Möginger et al., and Román-Cruz et al. as applied to claims 1, 2, 4, 8, 11, 20, 22, 25, 27, 29, 30, 33, 43, 44, 47, 48, and 58-60 above, and further in view of Shen et al. (Nature biotechnology. 2012 Feb; 30 (2): 184-189), all references of record, and Jaffe et al. (Bioconjugate Chemistry. 2019; 30: 47−53).
See the combined teachings in the prior art above. None of the references teach a linker comprising the following structure:
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84
192
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or linker binding (to one of the two proteins?) at a 3-position of succinimide.
Shen et al. teach the heterobifunctional maleimido caproyl linker structure recited in claim 56, see Supplemental Figure 10 (additionally depicting protein components on either side of the linker):
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103
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In the abstract, Figures 1, 3(c), 4, and S14-S16, Shen et al. describe providing a positively charged environment promoting hydrolysis of the succinimide ring in the linker, promoting enhancing the stability and therapeutic activity of the linker conjugate.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have bound a protein to the heterobifunctional maleimido caproyl linker at a 3-position of succinimide to enhance stability of the protein-linker-protein architecture. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have used the heterobifunctional maleimido caproyl linker of Shen et al. as the material bridging the Pf peptides and carriers of Sweere et al., Bollyky et al., Freschi et al., Seid et al., Masure et al., Ogunniyi et al., Pichichero, Möginger et al., and Román-Cruz et al. because Jaffe et al. teach using N-hydroxysuccinimide a linker between various peptides and CRM197 in paragraph bridging the columns on page 48 and Figure 1.
Applicant argues that none of the cited references, either alone or in combination, teach or suggest all the elements of amended claim 1 with any reasonable expectation of success.
Applicant points to Examples 2-4 and 9 of the application compare antibody titers in mice challenged with peptides conjugated to the carrier protein CRM-197 with or without Adjuvant A (a TLR4 agonist), Alum, or Adjuvant B (a TLR7/8 agonist). The results show that the highest antibody titers were obtained when the conjugates were adjuvanted with the TLR4 agonist. Examples 5 and 11 further show that administration of multivalent or admixed peptide conjugates produced high titers of cross-reactive antibodies when adjuvanted with Adjuvant A. Taken together, these data demonstrate that the claimed combination of Pf peptide conjugates with a TLR4 agonist adjuvant results in a surprising and unexpected effect of increased antibody titer.
Applicant’s arguments and the working examples have been fully considered and reviewed, but are found unpersuasive. Administration of Pf-conjugated peptides with an adjuvant taught by Sweere et al induces humoral immunity and reduces the incidence of would infections by half, see In “Antibodies directed against Pf4 prevent Pseudomonas aeruginosa (Pa) colonization” and Figures S14B and 7B. Román-Cruz et al. conjugate Pf peptide to CRM197 to enhance humoral immunity to the Pf peptide, see the abstract provided. Pichichero teach Hib capsular polysaccharide (polyribosyl ribitol phosphate PRP) conjugated to CRM-197 elicited increasingly stronger anti-PRP responses and after boosters anti-PRP antibody levels reached >1000 times pre-vaccination levels. See “CRM197” on page 2507. In “Formulation of vaccine antigens”, Ogunniyi et al. teach co-administration of antigens in a mixture of (TLR4 agonist) monophosphoryl lipid A (MPL) and aluminum phosphate (AlPO4) adjuvants elicit high antibody titers and induce significantly longer survival times, see the abstract, Table 1, and Table 2. All of the required components, Pf peptides conjugated to CRM197 carrier, combined with adjuvant MPL-A, are appreciated in the prior art for inducing high antibody titers and augmented humoral responses. Therefore, no unexpected result of achieving high antibody titers with Pf peptides conjugated to CRM197 carrier, combined with adjuvant MPL-A, is demonstrated.
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 SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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/Shanon A. Foley/ Primary Examiner, Art Unit 1671