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 .
Election/Restrictions
Applicant’s election with traverse of Group I (drawn to a formula II) is as of record. Applicant elected compound is as recited in claim 10, and having the following structure:
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corresponding claim 1’s genus when R is a polyoxazoline polymer wherein R2 is alkyl; Z is S; lipid is dimyristoylamide, reading on claims 1 and 10, as the species (e.g. see Reply filed on 07/09/2024). The elected species to reads on claim 1’s Formula III as follows, wherein: R is H; R2 is (CH2)mCH3; Z is S; L is CH2CH2C(O)N; and the lipid is -C14H29.
Pending claims 1, 6-10, 12-15, 21-26, and 35-36 have been examined on the merits.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/10/2025 has been entered.
Maintained Rejection with changes per claim Amendment and Cancelation
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, 6-7, 12, 15, 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Heyes, US 20110313017 (“Heyes”).
Regarding claim 1, Claim 1’s R is found in Heyes at [0311] “R1, a group at the initiation site”. Claim 1’s POZ moiety is found in Heyes formula II [0310].
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Heyes at [0311] teaches POZ is a polyoxazoline polymer “POZa is a
-[N(COX)CH2CH2]x-, and POZb is -[N(COX)CH2CH2]y-”. Claim 1’s X is R3 in formula II above and found in Heyes at [0311] “R3 is independently selected for each repeating unit of the polyoxazoline polymer and is a functional group including, but not limited to, unsubstituted or substituted alkyl, alkenyl, aralkyl and heterocycylalkyl.”
Claim 1’s subscripts n and a from POZ ([N(COX)CH2CH2]n}a) are found in Heyes at [0311] “"x" is an integer from 1-1000” and at [0320] Heyes discloses “ a is ran, which indicates a random copolymer, or block, which indicates a block copolymer.” Heyes also teaches at [0311] “…"y" is an integer from 0-1000, provided that if "y" is zero, then x is greater than 1 (i.e., when y is 0, then x is >1).”
Although, Heyes teaches a formula II containing two POZ groups: POZa and POZb, instead of one, Heyes also teaches compounds of formula II could also have one POZ group when y is zero, x is greater than 1. In that case POZb would not exist, leaving compounds of formula II with only one POZ group. Therefore, it would have been obvious to have a compound with only one POZ group because Heyes discloses various options for compounds of formula II to have either one POZ or two.
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Claim 1’s Z is S in formula II above.
Claim l's L is found in Heyes at [0314] "In one preferred embodiment of Formula 11, L is a linker is one of the following: -(CH2)X-, -(CH2)X-O-CO-NH- and -(CH2)X-CO-NH- (where x=l-10)". The alternative linker option “-(CH2)X-CO-NH-“ to which the DAA lipid portion is attached. In this structure, R1 and R2 are alkyl groups connected to the lipid portion, which in turn is linked through L to form a linker-lipid complex, to arrive at the claimed invention. It is then evident that L linker in POZ polymer has an amide group, -CO-NH-, which a person of ordinary skill in the art (POSITA) would expect to be susceptible to enzymatic cleavage such as amidase. Heyes differs from claim 1's L in that it teaches a genus including where -(CH2)X- where x=l-10.
However, Heyes teaches [0414] POZ-DAA conjugates containing a linker -(CH2)x- where X is 1. It would have been obvious to substitute -(CH2)- linker with -(CH2CH2)-, where x is 2, because Heyes discloses linkers with various lengths for compounds of formula II as found in [0314] -(CH2)x- where X=l-10, such substitutions are routine in the art, and have a homologous relationship thereby providing an expectation that the compounds would have similar properties (MPEP 2144.09).
Moreover, claim 1’s L having controllable degradability in physiological media. While Heyes does not explicitly use this term, but Heyes describes similar concept at [0304] “lipid moiety to form a hydrolytically stable linkage and, in turn, a hydrolytically stable POZ-DAA conjugate.” Heyes also teaches [0063] that “term "hydrolytically stable," as used herein, refers to a linkage that is stable in aqueous solutions under physiological conditions; in one embodiment, such linkages are stable for at least 12 hours, 24 hours, 48 hours, 96 hours, 192 hours or greater.” Despite its hydrolytically stable linker, it is reasonable one of ordinary skill in the art would recognize that some level of degradability is expected.
Claim 1’s lipid with at least one hydrophobic moiety is found in Heyes at [0024] “cationic lipid is selected from the group consisting of 1,2-dilinoley loxy-N,N-dimethy laminopropane (D LinD MA), 1,2-dilinoleny loxy-N,N-dimethy laminopropane (DLenDMA), 1,2-di-y-linolenyloxy-N,N-dimethylaminopropane (y-DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3 ]-dioxolane (DLin-K-C2-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3 ]-dioxolane (DLin-K-DMA).”
Regarding claim 6, claim 6’s, as indicated above in claim 1, R is found in Heyes at [0311] “R1, a group at the initiation site, is a member selected from the group consisting of hydrogen, alkyl, substituted alkyl, aralkyl or substituted aralkyl.” Whereas subscript n is the same as x and Heyes teaches that “"x" is an integer from 1-1000".
Regarding claim 7, claim 7’s having a rate of hydrolysis that is determined at least in part by L is found in Heyes at [0304] “lipid moiety to form a hydrolytically stable linkage and, in turn, a hydrolytically stable POZ-DAA conjugate.” Heyes also teaches [0063] that “term "hydrolytically stable," as used herein, refers to a linkage that is stable in aqueous solutions under physiological conditions.” It is then reasonable to expect the linker to have a low rate of hydrolysis.
Regarding claim 12, claim 12’s composition contains a cationic or ionizable lipid is found in Heyes at [0024] “cationic lipid is selected from the group consisting of 1,2-dilinoley loxy-N,N-dimethy laminopropane (DLinD MA), 1,2-dilinoleny loxy-N,N-dimethy laminopropane (DLenDMA), 1,2-di-y-linolenyloxy-N,N-dimethylaminopropane (y-DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3 ]-dioxolane (DLin-K-C2-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3 ]-dioxolane (DLin-K-DMA).”
Regarding claim 15, as applied to claim 12 above, claim 15’s R is found in Heyes at [0311] “R1, a group at the initiation site”. Claim 15’s POZ moiety is found in Heyes formula II [0310].
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Heyes at [0311] teaches POZ is a polyoxazoline polymer “POZa is a -[N(COX)CH2CH2]x -, and POZb is -[N(COX)CH2CH2]y –“. Claim 1’s X is R3 in formula II above and found in Heyes at [0311] “R3 is independently selected for each repeating unit of the polyoxazoline polymer and is a functional group including, but not limited to, unsubstituted or substituted alkyl, alkenyl, aralkyl and heterocycylalkyl.” Haeyes ([0017]) teaches that POZ
is can be either a random or block copolymer.
Claim 15’s subscripts n and a from POZ ([N(COX)CH2CH2]n}a) are found in Heyes at [0311 “"x" is an integer from 1-1000.” Heyes also teaches at [0311] “…"y" is an integer from 0-1000, provided that if "y" is zero, then x is greater than 1 (i.e., when y is 0, then x is >1).”
Although, Heyes teaches a formula II containing two POZ groups: POZa and POZb, instead of one. But Heyes also teaches compounds of formula II could also have one POZ group when y is zero, x is greater than 1. In that case POZb would not exist, leaving compounds of formula II with only one POZ group. Therefore, it would have been obvious to have a compound with only one POZ group because Heyes discloses various options for compounds of formula II to have either one POZ or two.
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Claim 15’s Z is S in formula II above.
Claim 15’s L is found in Heyes at [0314] “In one preferred embodiment of Formula II, L is a linker is one of the following: —(CH2)X—, —(CH2)X—O—CO—NH— and —(CH2)X—CO—NH— (where x=1-10)”. The alternative linker option “-(CH2)X-CO-NH-“ to which the DAA lipid portion is attached. In this structure, R1 and R2 are alkyl groups connected to the lipid portion, which in turn is linked though L to form a linker-lipid complex, to arrive at the claimed invention. It is evident that L linker in POZ polymer has an amide group, -CO-NH-, which a POSITA would expect to be susceptible to enzymatic cleavage such as amidase. Heyes differs from claim 1’s L in that it teaches a genus including where –(CH2)X- where x=1-10. However, Heyes teaches [0414] POZ-DAA conjugates containing a linker –(CH2)x- where X is 1. It would have been obvious to substitute –(CH2)- linker with –(CH2CH2)-, where x is 2, because Heyes discloses linkers with various lengths for compounds of formula II as found in [0314] –(CH2)x- where X=1-10.
Claim 15’s L having controllable degradability in physiological media. While Heyes does not explicitly use this term, but Heyes describes similar concept at [0304] “lipid moiety to form a hydrolytically stable linkage and, in turn, a hydrolytically stable POZ-DAA conjugate.” Heyes also teaches [0063] that “term "hydrolytically stable," as used herein, refers to a linkage that is stable in aqueous solutions under physiological conditions; in one embodiment, such linkages are stable for at least 12 hours, 24 hours, 48 hours, 96 hours, 192 hours or greater.” Despite its hydrolytically stable linker, it is reasonable one of ordinary skill in the art would recognize that some level of degradability is expected.
Claim 15’s lipid with at least one hydrophobic moiety is found in Heyes at [0024] “cationic lipid is selected from the group consisting of 1,2-dilinoley loxy-N,N-dimethy laminopropane (D LinD MA), 1,2-dilinoleny loxy-N,N-dimethy laminopropane (DLenDMA), 1,2-di-y-linolenyloxy-N,N-dimethylaminopropane (y-DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3 ]-dioxolane (DLin-K-C2-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3 ]-dioxolane (DLin-K-DMA).”
Regarding claim 21, claim 21’s composition contains a cationic or ionizable lipid is found in Heyes at [0024] “cationic lipid is selected from the group consisting of 1,2-dilinoley loxy-N,N-dimethy laminopropane (DLinD MA), 1,2-dilinoleny loxy-N,N-dimethy laminopropane (DLenDMA), 1,2-di-y-linolenyloxy-N,N-dimethylaminopropane (y-DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3 ]-dioxolane (DLin-K-C2-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3 ]-dioxolane (DLin-K-DMA).”
Regarding claim 22, claim 22’s having a rate of hydrolysis that is determined at least in part by L is found in Heyes at [0304] “lipid moiety to form a hydrolytically stable linkage and, in turn, a hydrolytically stable POZ-DAA conjugate.” Heyes also teaches [0063] that “term "hydrolytically stable," as used herein, refers to a linkage that is stable in aqueous solutions under physiological conditions.” It is then reasonable to expect the linker to have a low rate of hydrolysis.
Claims 8-9, 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Heyes as applied to claims 1-7, 11-12, 15-22 above and further in view of Manoharan et al. US20180065920 A1 (“Manoharan”).
Regarding claim 8, Heyes does not explicitly teach hydrolysis half-life in 50 percent human plasma of about 10 minutes or less.
How this concept is found in Manoharan at [0266] “a cationic lipid of any of the embodiments described herein has an in vivo half-life (t1/2 ) (e. g., in the liver , spleen or plasma ) of less than about 3 hours… less than about 0.5 hour or less than about 0.25 hours.” It would have been obvious to one of ordinary skill in the art at the time of this application’s filing to utilize the compound disclosed by Heyes, comprising various lipid moieties and linkers utilized in similar conjugates for delivery of target material at a desired rate, as disclosed by Manoharan.
Note: Manoharan is an ‘analogous art’ because Manoharan and Heyes are in a similar field of use, such as biopolymers, making it reasonable for one ordinary skill in the art to consider combining them.
Regarding claim 9, claim 9’s hydrolysis half-life in 50 percent human plasma of about 120 hours or more is found in Heyes at [0304] “lipid moiety to form a hydrolytically stable linkage and, in turn, a hydrolytically stable POZ-DAA conjugate.” Heyes also teaches at [0063] “The term "hydrolytically stable," as used herein,
refers to a linkage that is stable in aqueous solutions under physiological conditions; in one embodiment, such linkages are stable for at least 12 hours, 24 hours, 48 hours, 96 hours, 192 hours or greater.” It would have been obvious to one of ordinary skill in the art at the time of this application’s filing to utilize the compounds disclosed by Heyes, comprising various lipid moieties and linkers utilized in similar conjugates for delivery of target material at a desired rate, as disclosed by Manoharan, and determine the relative stability of said linkers in human plasma for extended lengths.
Regarding claim 23, Heyes does not explicitly teach hydrolysis half-life in 50 percent human plasma of about 10 minutes or less.
How this concept is found in Manoharan at [0266] “a cationic lipid of any of the embodiments described herein has an in vivo half-life (t1/2 ) (e. g., in the liver , spleen or plasma ) of less than about 3 hours… less than about 0.5 hour or less than about 0.25 hours.” It would have been obvious to one of ordinary skill in the art at the time of this application’s filing to utilize the compound disclosed by Heyes, comprising various lipid moieties and linkers utilized in similar conjugates for delivery of target material at a desired rate, as disclosed by Manoharan.
Note: Manoharan is an ‘analogous art’ because Manoharan and Heyes are in a similar field of use, such as biopolymers, making it reasonable for one ordinary skill in the art to consider combining them.
Regarding claim 24, claim 24’s hydrolysis half-life in 50 percent human plasma of about 120 hours or more is found in Heyes at [0304] “lipid moiety to form a hydrolytically stable linkage and, in turn, a hydrolytically stable POZ-DAA conjugate.” Heyes also teaches at [0063] “The term "hydrolytically stable," as used herein, refers to a linkage that is stable in aqueous solutions under physiological conditions; in one embodiment, such linkages are stable for at least 12 hours, 24 hours, 48 hours, 96 hours, 192 hours or greater.” It would have been obvious to one of ordinary skill in the art at the time of this application’s filing to utilize the compounds disclosed by Heyes, comprising various lipid moieties and linkers utilized in similar conjugates for delivery of target material at a desired rate, as disclosed by Manoharan, and determine the relative stability of said linkers in human plasma for extended lengths.
Claims 13-14, 25-26 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Heyes and Manoharan as applied to claims 1-12 and 15-24 above in further view of Harris et al. WO2020264505A1 (“Harris”).
Regarding claim 13 and 14, the combined teachings of Heyes and Manoharan do not explicitly teach exhibiting a change of about 30 percent to about 50 or about 10 percent or less in POZ-DMA peak area as measured by UV.
However, Harris teaches a similar concept as found in page 68, line 14-31, “The samples (POZ/PEG/dextran) were analyzed by HPLC, …using UV detector… a calibration curve was created for each drug tested using a peak area versus concentration curve to determine the concentration of hydrolyzed drug at each time point.” It is important to indicate that the specification discloses at (100, line 16-21) “After overnight hydrolysis, methanol was added, the samples were centrifuged, and the supernatants were transferred to HPLC vials.” Although Harris does not mention specific wavelength, it would have been obvious to one ordinary skill in the art to consider that a similar wavelength was used for the HPLC analysis, given that both the Applicant and prior art use HPLC to monitor the degradation of POZ drugs. The prior art is considered “analogous art” and can combine with instant application because it falls within the same field of biopolymer. Specifically, the prior art focuses on polyoxazoline lipid conjugates, methods of synthesis, and pharmaceutical compositions, which are closely related to the technology in the instant application. Because of this close relationship, one of ordinary skill in the art would consider combining them.
Regarding lipo-amidase, Harris teaches at page 68, line 24-25, “POZ drug conjugate and the released drug from the crashed plasma proteins.” Given that POZ drugs were incubated with plasma to monitor drug release, and that plasma contains amidases, therefore it would have been obvious to one ordinary skill in the art to consider that these enzymes can contribute to the degradation process, resulting in the release of POZ drugs. Therefore, it is obvious that the HPLC peak for POZ drug could be lower due to degradation and a decrease in its level.
Regarding claim 25 and 26, the combined teachings of Heyes and Manoharan do not explicitly teach exhibiting a change of about 30 percent to about 50 or about 10 percent or less in POZ-DMA peak area as measured by UV.
However, Harris teaches a similar concept as found in page 68, line 14-31, “The samples (POZ/PEG/dextran) were analyzed by HPLC, …using UV detector… a calibration curve was created for each drug tested using a peak area versus concentration curve to determine the concentration of hydrolyzed drug at each time point.” It is important to indicate that the specification discloses at (100, line 16-21) “After overnight hydrolysis, methanol was added, the samples were centrifuged, and the supernatants were transferred to HPLC vials.” Although Harris does not mention specific wavelength, it would have been obvious to one ordinary skill in the art to consider that a similar wavelength was used for the HPLC analysis, given that both the Applicant and prior art use HPLC to monitor the degradation of POZ drugs. The prior art is considered “analogous art” and can combine with instant application because it falls within the same field of biopolymer. Specifically, the prior art focuses on polyoxazoline lipid conjugates, methods of synthesis, and pharmaceutical compositions, which are closely related to the technology in the instant application. Because of this close relationship, one of ordinary skill in the art would consider combining them. Furthermore, it would have been obvious to a person skilled in the art to recognize the need to measure the peak area for any linker subject to degradation.
Regarding lipo-amidase, Harris teaches at page 68, line 24-25, “POZ drug conjugate and the released drug from the crashed plasma proteins.” Given that POZ drugs were incubated with plasma to monitor drug release, and that plasma contains amidases, therefore it would have been obvious to one ordinary skill in the art to consider that these enzymes can contribute to the degradation process, resulting in the release of POZ drugs. Therefore, it is obvious that the HPLC peak for POZ drug could be lower due to degradation and a decrease in its level.
Furthermore, the concept of measuring peak area would still apply to the broader “change in peak area” limitation, encompassing any area of interest in evaluating molecular integrity. Therefore, a person of ordinary skill in the art would recognize the same analytical approach and rational for measuring POZ-DMA peak area would be applicable to measuring changes in peak for any relevant molecular component.
Regarding claims 35 and 36, Heyes teaches Z is S and does not teach to be either N or O.
However, Patani (page 3155, section B.; Figure 21) teaches that both S and O are divalent isosteres and have been used extensively in the study of the structure-activity relationships of various pharmacologically active agents. Given that both S and O share similar electronic and steric properties, thus a person of ordinary skill in the art would have been motivated to combine the teaching of Heyes and Patini to exchange S with O to enhance the compound’s overall properties while maintaining its core structure and arrive at the claimed invention wherein Z is O. This substitution would optimize and fine-tune the properties of the compound such as improving the compound efficacy, stability, and bioavailability; leading to the development of a more effective and safer therapeutic agent.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Subject Matter Free of the Art of Record
Claim 10 is free of the art of record. The closest prior art is Heyes, James US20110313017A1 (“Heyes”). While Heyes teaches various formulas resembling the claimed invention, however Heyes does not teach any compounds similar to the claimed compound. Claim 10 is not allowed because it relies on claims that have been rejected. As a result, until this issue is remedied or resolved, the claim cannot be subject of allowance.
Response to Argument
Improper Finality
If Applicant believes that the Final Office Action was improper, Applicant may file a petition for withdrawal with the Office.
The Rejections Under 35 U.S.C. § 103
Applicant argues that Heyes’ teachings do not explicitly teach an amidase-cleavable as linking group and that the lipid has one or more alkyl chains. Applicant’s argument is not persuasive, because Heyes ([0311]-[0315]) teaches “In one preferred embodiment of Formula II, L is a linker is one of the following: —(CH2)X—, —(CH2)X—O—CO—NH— and —(CH2)X—CO—NH— (where x=1-10)”. Therefore, it would have been obvious to a POSITA that an amide functional group is a substrate for amidase enzymes in physiological environment, whether Heyes explicitly disclosed such mechanism. Regarding lipid moiety, Heyes (page 2, [0021]) discloses “wherein: R1 and R2 are independently selected and are alkyl groups having from about 10 to about 20 carbon atoms,” directly indicating two distinct alkyl substituents, R1 and R2, as integral components of lipid structure. Therefore, contrary to Applicant’s assertion, Heyes explicitly discloses both an amide functional group within the linker couple with a lipid moiety with two alkyl chains.
Conclusion
Therefore, claims 1, 6-9, 12-15, 21-26, and 35-36 are rejected.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622