DETAILED ACTION
The instant application is a U.S. National Phase of PCT/IB2022/058392, filed 9/7/2022. Applicant’s Preliminary Amendment, filed 3/14/2024, is acknowledged.
Claims 1-5 remain pending. Claims 4-5 are currently amended.
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 claims foreign priority to IN202141040608, filed 9/7/2021, and an English translation was provided 3/6/2024. Accordingly, the effective filing date of the instant application is 9/7/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/21/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract submitted on 3/6/2024 is not a single paragraph, includes bullet points, and is ungrammatical, e.g., line 4 recites “comprises the step of” then lists multiple steps and “Present invention also relates…” in line 9 is missing an article at the beginning of the sentence.
Claim Objections
Claims 1-5 are objected to because of the following informalities:
Claims 1-3 comprise an internal period after the recitation of “parent nucleus” in line 3.
The internal periods after steps (a)-(b) should be removed from claim 1-3. Steps (a)-(c) can be amended to instead recite “a),” “b),” and “c)” to overcome this objection.
In Claims 1-5, the comma recited after “wherein” is ungrammatical and should be deleted.
In Claim 2, the comma recited after “(FR901379)” in line 2 should be deleted.
In Claim 3, the comma recited after “Echinocandin B” in line 1 should be deleted.
In Claims 1-5, the following capitalized words should be made lower-case: “Wherein,” “Aggregation,” “Cross-linking,” “Isolation,” “Micafungin,” “Echinocandin,” “Polyethyleneimine,” and “Glutaraldehyde”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claims 1-5 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
Scope of the claimed genus. Claim 1 embraces a method for converting echinocandins into echinocandin parent nucleus by treating cross-linked deacylase cells with echinocandins to yield desired echinocandin parent nucleus; wherein the cross-linking of deacylase cells involves: a) aggregation of deacylase cells; b) cross-linking of aggregated cells; and c) isolation of cross-linked cells. Echinocandins and echinocandin parent nucleus are recited extremely broadly. The specification does not provide a definition for “echinocandin parent nucleus.” The steps of aggregation of deacylase cells, cross-linking of aggregated deacylase cells, and isolation of cross-linked deacylase cells are recited at a high level of generality.
Claim 2 embraces a method for converting micafungin I intermediate (FR901379) into micafungin II intermediate (FR179642) by treating cross-linked deacylase cells with echinocandins to yield desired echinocandin parent nucleus; wherein the cross-linking of deacylase cells involves: a) aggregation of deacylase cells; b) cross-linking of aggregated cells; and c) isolation of cross-linked cells. Echinocandins and echinocandin parent nucleus are recited extremely broadly. The specification does not provide a definition for “echinocandin parent nucleus.” The steps of aggregation of deacylase cells, cross-linking of aggregated deacylase cells, and isolation of cross-linked deacylase cells are recited at a high level of generality.
Claim 3 embraces a method for converting echinocandin B into echinocandin B nucleus by treating cross-linked deacylase cells with echinocandins to yield desired echinocandin parent nucleus; wherein the cross-linking of deacylase cells involves: a) aggregation of deacylase cells; b) cross-linking of aggregated cells; and c) isolation of cross-linked cells. Echinocandins and echinocandin parent nucleus are recited extremely broadly. The specification does not provide a definition for “echinocandin parent nucleus.” The steps of aggregation of deacylase cells, cross-linking of aggregated deacylase cells, and isolation of cross-linked deacylase cells are recited at a high level of generality.
Claim 4 depends from claim 1 and recites the aggregation step is performed using polyethyleneimine. Claim 5 depends from claim 1 and recites the cross-linking step is performed using glutaraldehyde.
State of the prior art. The state of the art at the time of the invention demonstrates that acylase from the fungus Actinoplanes utahensis NRRL 12052 catalyzes the reaction of echinocandin species; however, acylase is not unique to fungal strains.
Hashimoto (J. Antibiot., 2009, Vol. 62, pp.27-35) teaches micafungin is semi-synthesized from acylated cyclic hexapeptide FR901379, a natural product from the fungus Coleophoma empetri F-11899, through deacylation of FR901379, followed by chemical reacylation with the optimized N-acyl side chain (see Abstract, p.27, right column, 1st passage, passage bridging pp.27-28, and Figs. 1 and 2). Echinocandins are a class of antifungal drugs derived from echinocandin B from the filamentous fungi Aspergillus nidulans var. echinulatus (see p.62, paragraph bridging left and right columns, right column, 1st paragraph, and Fig. 1). Treatment of FR901379 with acylase from Actinoplanes utahensis removes a palmitoyl group and yields FR179642 (see p.29, paragraph bridging left and right column, p.32, left column, 1st passage, and Fig. 2).
Shao et al. (Appl. Environ. Microbio., 2013, Vol. 79(4), pp.1126-1133) teaches that anidulafungin is an antifungal drug derived from echinocandin B nucleus (see Abstract, p.1126, left column, 2nd paragraph, and p.1132, left column, last paragraph). Deacylation of echinocandin B by deacylase from Actinoplanes utahensis NRRL 12052 leads to the formation of echinocandin B nucleus, a precursor of many antifungal agents (see p.1126, left column, last paragraph, and Fig. 1). A. utahensis deacylase catalyzes the cleavage of the linoleoyl side chain from echinocandin B and also mediates the cleavage of aculeacin A, FR901379, a semisynthetic echinocandin B derivative (see p.1126, paragraph bridging left and right columns). Shao et al. teach enzymatic deacylation is rate-limiting when performed using whole cells of A. utahensis, presumed to be due to a low production of echinocandin B deacylase (see p.1126, right column, 1st paragraph). Shao et al. demonstrated increased deacylation of echinocandin B into echinocandin B nucleus by overexpression of the echinocandin B deacylase gene in A. utahensis and Streptomyces lividans TK24 and S. albus (see p.1126, right column, 1st paragraph). Shao et al. observed enhanced production of echinocandin B nucleus in the recombinant S. lividans and S. albus strains as well as the recombinant A. utahensis strain overexpressing echinocandin B deacylase as compared to wild-type A. utahensis NRRL 12052 (see p.1131, left column, 1st passage,-right column, 1st passage, and Figs. 5-6). Thus, Shao et al. demonstrated echinocandin B deacylase from A. utahensis can be recombinantly expressed to control production of echinocandin B deacylase and improve deacylation in whole cells.
Shivakumar et al. (3 Biotech, 2019, Vol. 9:412, pp.1-6) teach that anidulafungin is a new class of antifungal agent derived from echinocandin B nucleus, an intermediate metabolite of echinocandin B produced by Aspergillus nidulans (see Abstract and p.1, right column, 1st passage). Echinocandins are synthetically modified non ribosomal cyclic hexapeptides conjugated with a fatty acid (see p.1, left column, 1st passage). Caspofungin, micafungin, and anidulafungin are three semisynthetic echinocandins (see p.1, right column, 1st passage). Echinocandin B is synthesized by fungus and when deacylated forms echinocandin B nucleus—a cyclic hexapeptide without a linoleoyl side chain—which forms anidulafungin by subsequent chemical reacylation (see p.1, right column, 1st passage). Deacylation of echinocandin B into echinocandin B nucleus is catalyzed by acylase, also known as deacylase, endogenous to Actinoplanes utahensis NRRL 12052 (see p.2, left column, 1st passage). Shivakumar et al. screened 140 bacteria belonging to Actinomycetes, isolated from tropical soil (see Abstract, p.2, left column, 1st paragraph, and paragraph bridging left and right columns, right column, 2nd passage). Fifty-three strains were found to be acylase positive and selected for quantitative assay (see p.2, right column, 3rd passage, p.3, right column, 4th passage,- p.4, left column, 1st passage, p.5, right column, last passage, and Figs. 2-7). Shivakumar et al. thereby demonstrated that acylases are not unique to fungus and can be found in Actinomycete bacterial species.
Summary of species disclosed in the original specification. MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Example 1 demonstrates the conversion of micafungin I intermediate FR17901379 into micafungin II intermediate FR179642 and the conversion of anidulafungin I to anidulafungin II. Example 2 demonstrates the scale up of the conversions demonstrated in Example 1 to kiloliter quantities. Step 1 of Example 1 describes the seed fermentation conditions and medium along with the inoculation amount. However, the Step 1 does not elucidate what the seed fermenter is inoculated with for cultivation. Step 2 of Example 1 describes the production fermentation conditions and medium along with the inoculation amount. However, Step 2 does not elucidate what the production fermenter is inoculated with for cultivation. Step 3 of Example 1 describes the aggregation of cells by adding polyethyleneimine directly to the fermenter under constant mixing. Step 4 of Example 1 describes the crosslinking of cells after cell aggregation by adding glutaraldehyde directly to the fermenter under constant mixing. Step 5 of Example 1 describes the filtration, washing, and drying of the crosslinked cell aggregates. The protocol for testing the activity of crosslinked cell aggregates is given. Step 6a of Example 1 describes the protocol and conditions for conversion of micafungin I intermediate FR901379 into micafungin II intermediate FR179642 and sets forth the crosslinked cell aggregates are deacylase crosslinked cell aggregates. The deacylase crosslinked cell aggregates are combined and mixed with micafungin I intermediate FR901379 solution in a reactor. After completion of the reaction, the reaction mixture is harvested and the crosslinked cell aggregates are separated by filtration, washed, and dried. Step 6b of Example 1 describes the protocol and conditions for conversion of anidulafungin I intermediate into anidulafungin II intermediate and sets forth the crosslinked cell aggregates are deacylase crosslinked cell aggregates. The deacylase crosslinked cell aggregates are combined and mixed with anidulafungin I intermediate solution in a reactor. After completion of the reaction, the reaction mixture is harvested and the crosslinked cell aggregates are separated by filtration, washed, and dried. The examples do not disclose what type of cells are inoculated and cultured in the seed and production fermenters, only later in Steps 6a and 6b it is vaguely mentioned that the cells are deacylase cells. However, it is not specified which exact deacylase is reduced to practice in the Examples and what cells the deacylase is cultured in. The specification only generally discloses that Actinoplanes utahensis is known to produce deacylase (see p.3, 1st passage), but the examples did not specify that A. utahensis was cultivated. Furthermore, it is not clear what anidulafungin I intermediate or anidulafungin II intermediate are because they are not adequately described or disclosed in the specification. The specification discloses that anidulafungin is generated by enzymatic deacylation of echinocandin B to a cyclic hexapeptide without a linoleoyl side chain by subsequence chemical reacylation, but does not elaborate on any intermediates (see p.2, last passage). Thus, it is not exactly clear what echinocandin compounds denoted as anidulafungin intermediates were bio-converted in Step 6b. Given the potential variability encompassed by the genera of deacylase enzymes and echinocandin compounds, this disclosure cannot be considered representative of the genera of deacylase enzymes and echinocandin compounds.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. As noted above, the art teaches that Actinoplanes utahensis NRRL 12052 echinocandin B deacylase catalyzes the deacylation of echinocandin B, FR901379, among other echinocandin species. However, due to the lack of details in the instant specification regarding which deacylase is used—that of A. utahensis or a bacterial homolog—, what the chemical structures of the anidulafungin intermediates are, and whether the bioconversions were performed using whole cells or isolated enzyme, Applicant has not established sufficient written description for the claimed invention.
For all the reasons presented above, one of skill in the art would not know which of the possible deacylase enzymes and echinocandin compounds are adaptable to the claimed inventions. Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of the genus of echinocandins and deacylase enzymes as broadly claimed.
Given the lack of disclosure of what deacylase was used and what the chemical structures of the anidulafungin intermediates were, the recognizable description of 1 bioconversion species, and the fact the species that was described cannot be considered representative of the broad genus, applicant was not in possession of the invention as claimed.
Claim Rejections - 35 USC § 112(b)
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 1-5 are 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.
Claims 1-3 recite “echinocandin parent nucleus” in line 3 of each claim. It is not clear what “echinocandin parent nucleus” intends to refer to and the specification has not defined the term. The term is not recognized in the art. Thus, one of ordinary skill in the art would not be able to determine the metes and bounds of the claim limitation. Applicant may amend the claims to remove the claim limitation and instead recite the specific echinocandin molecule that is yielded by deacylation.
Claims 1-3 recite “deacylase cells” in line 2 and step a) of each claim. It is not clear if this claim limitation is intended to refer to whole cells in which a deacylase enzyme is expressed or if deacylase provided in any medium would read on the claim limitation. The specification has not defined the claim limitation and the phrase is not standard in the relevant art. Therefore, one of ordinary skill in the art would not be able to determine the metes and bounds of the claim limitation.
Claims 4-5 are also rejected for being dependent on a rejected base claim and failing to remedy the issues set forth above.
Claim 2 recites the broad limitations “Micafungin I intermediate” and “Micafungin II intermediate” followed by the narrower limitations “FR901379” and “FR179642”, respectively, in parentheses. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claim. Thus, it is not clear if the parenthetical limitations are required features of the claim or if any micafungin intermediates would satisfy the claim limitation. Therefore, one of ordinary skill in the art would not be able to determine the metes and bounds of the claim.
Claim Interpretation
In view of the 35 U.S.C. 112(b) rejections set forth above, the following claim limitation interpretations are set forth for the application of art to the claims:
The term echinocandin parent nucleus is being interpreted as an echinocandin molecule obtained by the catalyzed reaction of deacylase (e.g., echinocandin B nucleus, FR179642).
The term deacylase cells is being interpreted as any active form of deacylase enzyme including whole cells expressing deacylase and isolated deacylase enzyme.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2 and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CN108441529 to Yuan et al. (of record in IDS filed 6/21/2024; citations corresponding to PE2E machine translation provided; hereby referred to as Yuan1).
Regarding claims 1-2 and 5, Yuan1 teaches a method of converting FR901379 into FR179642 by reacting FR901379 with a cross-linked acyl enzyme (see Abstract, p.3, 2nd-7th passages, and Claim 1). Yuan1 teaches obtaining an echinocandin B acyl enzyme, reading on deacylase, from a fermented genetically-engineered bacteria by filtering or centrifuging the fermentation broth, and collecting the crude enzyme, reading on aggregation of deacylase cells (see p.3, 5th-6th and 8th-9th passages). Yuan1 further teaches the collected crude echinocandin B acyl enzyme is cross-linked with glutaraldehyde, reading on claim 5 (see p.3, 11th passage, Examples 3-5, and Claims 2-4). The cross-linked crude echinocandin acyl enzyme is considered to be isolated since the enzyme has been retrieved from fermented cells, reading on isolation of cross-linked cells. Thus, Yuan1 anticipates claims 1-2 and 5 of the instant invention.
Claims 1, 3, and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CN108410929 to Yuan et al. (of record in IDS filed 6/21/2024; citations corresponding to PE2E machine translation provided; hereby referred to as Yuan2).
Regarding claims 1, 3 and 5, Yuan2 teaches a method of converting echinocandin B into echinocandin B mother nucleus by reacting the echinocandin B with a cross-linked deacylation enzyme (see Abstract, p.3, 8th-11th passages, and Claim 1). Yuan2 teaches the deacylase enzyme is obtained by fermentation of a genetically-engineered bacteria, the fermentation broth is filtered or centrifuged, and collecting the crude deacylation enzyme, reading on aggregation of deacylase cells (see p.3, 8th-13th passages). The crude deacylation enzyme collected is then cross-linked with glutaraldehyde as a cross-linking agent, reading on claim 5 (see p.4, 2nd passage, and Claim 1). The cross-linked crude deacylation enzyme is considered to be isolated since the enzyme has been retrieved from fermented cells, reading on isolation of cross-linked cells. Thus, Yuan2 anticipates claims 1, 3, and 5 of the instant invention.
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over CN108441529 to Yuan et al. (of record in IDS filed 6/21/2024; citations corresponding to PE2E machine translation provided; hereby referred to as Yuan1), as applied to claims 1-2 and 5 above, and further in view of Lopez-Gallego et al. (Biomacromol., 2005, Vol. 6, pp.1839-1842).
Yuan1 teaches the invention of claim 1 as outlined in the rejection above.
Regarding claim 4, Yuan1 does not teach the aggregation is performed using polyethyleneimine.
Lopez-Gallego teaches a novel method of preparing glutaraldehyde cross-linked enzyme aggregates of glutaryl acylase by co-aggregation of the enzyme with polyethyleneimine, which resulted in a very stable immobilized enzyme with improved enzymatic activity and prevented release of the enzyme from the aggregate (see Abstract, p.1840, right column, 1st-2nd and last paragraphs, p.1841, left column, 1st paragraph, paragraph bridging left and right columns, p.1842, left column, last paragraph, right column, 1st paragraph, and Fig. 2).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have co-aggregated with polyethyleneimine and cross-linked with glutaraldehyde, as taught by Lopez-Gallego, the echinocandin B acyl enzyme of Yuan1, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to improve stability of the enzyme immobilization and improve activity of the immobilized enzyme, yielding predictable results. There would have been a reasonable expectation of success because Lopez-Gallego teaches the method improved stability of an acylase enzyme and echinocandin B acyl enzyme is also an acylase. Thus, claim 4 is prima facie obvious.
Conclusion
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/J.P.S./Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651