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 .
Status of the Application
1. Claims 1-47 are pending and subject to examination on the merits.
Priority
2. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 63/426,206 filed 17 November 2022.
Claim Objections
3. Applicant is advised that should claim 7 be found allowable, claim 8 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
4. Claim 7 recites the limitation "wherein enzyme." There appears to be an apparent typographical error, where “wherein enzyme,” should be amended to “wherein the enzyme.”
5. Claim 20 is objected to because of the following informalities: “said labeling substrate liquid chromatography” should be amended to “said labeling substrate to a liquid chromatography” to improve grammar. Additionally, “quantifying amount” should be amended to “quantifying the amount.” Appropriate correction is required.
6. Applicant is advised that should claim 25 be found allowable, claim 26 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
7. Claim 25 recites the limitation "wherein enzyme." There appears to be an apparent typographical error, where “wherein enzyme,” should be amended to “wherein the enzyme.”
Claim Rejections - 35 USC § 112(a)
8. 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.
Written Description:
9. Claims 1-5, 7-11, 13-29, and 31 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 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.
The claims are drawn to a method to assay the activity of an enzyme, any enzyme by contacting the enzyme with an unspecified donor and unspecified labeling substrate to form a sample, incubating the sample, and then utilizing liquid chromatography (any variety) and quantifying an amount of labeling substrate after chromatography.
MPEP 2163(1):
35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en bane); Vas-Gath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111, 1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim's enablement is not equally conclusive of that claim's satisfactory written description"). The written description requirement has several policy objectives. "[T]he 'essential goal' of the description of the invention requirement is to clearly convey the information that an applicant [inventor] has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). "The 'written description' requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor's obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee [inventor] was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent's term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Gath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. However, a showing of possession alone does not cure the lack of a written description. Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 969-70, 63 USPQ2d 1609, 1617 (Fed. Cir. 2002). For example, it is now well accepted that a satisfactory description may be found in originally-filed claims or any other portion of the originally-filed specification. See In re Koller, 613 F.2d 819, 204 USPQ 702 (CCPA 1980); In re Gardner, 475 F.2d 1389, 177 USPQ 396 (CCPA 1973); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). However, that does not mean that all originally-filed claims have adequate written support. The specification must still be examined to assess whether an originally-filed claim has adequate support in the written disclosure and/or the drawings.
10. The claims are drawn to a method to assay the activity of an enzyme, any enzyme by contacting the enzyme with an unspecified donor and unspecified labeling substrate to form a sample, incubating the sample, and then utilizing liquid chromatography (any variety) and quantifying an amount of labeling substrate after chromatography. The variability in the number of enzymes, labeling substrates, donors, chromatography techniques, and quantification techniques is enormous. The specification does not describe a general methodology of assaying any enzyme for activity, utilizing any substrate, labeling substrate, and chromatography method. At most, the specification describes an assay to measure the activity of beta-1,4 galactosyltransferase 1 utilizing the fluorescent probe, 2-aminobenzamide, which labels glycans in combination with HILIC-MS to detected said labeled glycans, where the donor substrate is UDP-Gal. The reaction was analyzed using an Acquity UPLC I-Class coupled with a Vion IMS Q-Tof, and the chromatography column utilized is a Waters Acquity UPLC Glycoprotein BEH Amide chromatographic column. However, this very specific example is not all encompassing of any/all enzymes or any galactotransferase family of enzymes. How any enzyme utilizes its substrate and quantification thereof is highly specific, and the one demonstration in the specification does not exemplify this highly complex and individualized activity of any other enzyme. Here the specification is incomplete and it mandates that those skilled in the art must then figure out how to utilize the aimed invention. Thus, the claims do not find adequate support in any place in the specification to show that possession of methods for assaying the activity of any enzyme, with any substrate and any labeling substate, and any quantification methods. The courts have established:
Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336 (Fed. Cir. 2013):
A patent, however, "is not a reward for the search, but compensation for its successful conclusion." Ariad, 598 F.3d at 1353 (quoting University of Rochester, 358 F.3d at 930 n.10). For that reason, the written description requirement prohibits a patentee from "leaving it to the ... industry to complete an ufinished invention.” Id.
Enablement:
11. Claims 1-5, 7-11, 13-29, and 31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a specific method to assay the activity of beta-1,4 galactosyltransferase 1 utilizing the fluorescent probe, 2-aminobenzamide, which labels glycans in combination with HILIC-MS to detected said labeled glycans, where the donor substrate is UDP-Gal by utilizing an Acquity UPLC I-Class coupled with a Vion IMS Q-Tof and a Waters Acquity UPLC Glycoprotein BEH Amide chromatographic column, does not reasonably provide enablement for any/all enzymes (or the superfamily of galactotransferases, substrates, labeling substrates, chromatography methods, mass spectrometry methods, and quantification methods. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims without significant undue experimentation.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states:
"Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims in their broadest are drawn a method to assay the activity of an enzyme, any enzyme by contacting the enzyme with an unspecified donor and unspecified labeling substrate to form a sample, incubating the sample, and then utilizing liquid chromatography (any variety) and quantifying an amount of labeling substrate after chromatography. The direction and guidance coupled with the working examples of the application, however, are drawn only to a method to assay the activity of beta-1,4 galactosyltransferase 1 utilizing the fluorescent probe, 2-aminobenzamide, which labels glycans in combination with HILIC-MS to detected said labeled glycans, where the donor substrate is UDP-Gal by utilizing an Acquity UPLC I-Class coupled with a Vion IMS Q-Tof and a Waters Acquity UPLC Glycoprotein BEH Amide chromatographic column. The quantity experimentation would be considerable because, while the relative skill level in the art is high (PhD or MD), they would be required to ascertain which enzymes or combination of enzymes, substrates, to use. It would be extremely difficult to be able to discern what enzymes, substrates, labeling substates, chromatographic methods, mass spectrometry methods, and quantification methods thereof to choose to assay an enzyme’s activity. It would be almost impossible to reliably predict the combination and/or combinations necessary to assay the activity of any enzymes and quantify said activity.
Claim Rejections - 35 USC § 112(b)
12. 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.
13. Claims 7, 14, 25, 32, and 47 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 (s for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
14. The term “coupled online” in claim 14 is a relative term which renders the claim indefinite. The term “coupled online” is indefinite because there is no definition of online coupling in the specification or claim. For examination purposes, the broad but reasonable interpretation will be that the mass spectrometry technique for quantification will be performed after the liquid chromatography method on the separated substrates.
15. The term “coupled online” in claim 32 is a relative term which renders the claim indefinite. The term “coupled online” is indefinite because there is no definition of online coupling in the specification or claim. For examination purposes, the broad but reasonable interpretation will be that the mass spectrometry technique for quantification will be performed after the liquid chromatography method on the separated substrates.
16. The term “about” in claim 47 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, and the specification does not provide a standard for ascertaining the requisite degree. The specification states that about “should be understood to permit standard variation,” but there is no mention of the standard variation parameters, i.e. in the specific claim, how much variation (seconds, minutes, range) is permitted from each explicitly stated timepoint.
Claim Rejections - 35 USC § 102
17. 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.
18. 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.
19. Claims 1-2, 5, 7-11, 13-16, 19-20, 23, 25-29, 31-34, 37, 39, 46, and 47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Elkashef et al (Elkashef et al., 2016, Analyst—cited on the IDS dated 29 April 2024). Regarding claims 1-2, 5, 7-11, 13-15, 19-21, 23, 25-29, 31-34, , 37, 39, and 46-47, drawn to a method for assaying an enzyme, specifically a glycosyltransferase (claim 37), where the enzyme is incubated with a mixture of a glycosyl donor, glycosyl acceptor, which is specifically a glycan (claim 39), and a labeling substrate, where the incubated mixture is subjected to a liquid chromatographic column (claims 2 and 20) for separation and further quantified via fluorescence spectroscopy, wherein the enzyme is a naturally occurring enzyme (claim 5), which catalyzes glycosylation (claims 7-10, 23, 25-29), wherein said labeling substate is detected by fluorescence (claim 11) mass spectrometry coupled with liquid chromatography, specifically HPLC, for separation (claims 13-16, 31-34, and 46), and wherein the incubation of enzyme and substrate is 0-60 minutes (claim 47), Elkashef et al. teaches the optimization of the human polytransferase (Poly-ST), a naturally occurring enzyme responsible for polySia biosynthesis, where the enzyme is incubated with DMB-DP3, made up of alpha-2,8-linked sialic acid (DP3) conjugated to a 1,2-diamino-4,5-methylenedioxybenzene (DMB) label (Introduction, p. 5849, column 1, paragraphs 1-2; p. 5850, column 1, paragraphs 1). Specifically, DP3 and DMB is conjugated and then incubated with polyST enzyme overnight, where aliquots were taken at 1, 2, 4, 6, and 24hrs and subsequently analyzed by anion exchange HPLC and then polyST activity was quantified via reversed phase chromatography with a fluorescence detector (p. 5850, column 2, full paragraphs 3-5).
Claim Rejections - 35 USC § 103
20. 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.
21. Claims 1-47 are rejected under 35 U.S.C. 103 as being unpatentable over Montasser et al (Montasser et al., 2021, Science—cited herein) and Jung et al. (Jung et al., 2021, Engineering mammalian cell line for N-linked glycosylation control—cited herein). Regarding claims 1, 19, 37, and 47, drawn to a method of quantifying or characterizing the activity of a glycosyltransferase, comprising: (a) incubating a mixture with a glycosyl donor from 0-60 minutes, glycosyl acceptor, including a fluorescent label, and a glycosyltransferase capable of transferring a saccharide from the donor to the acceptor forming a product, (b) subjecting the mixture to chromatographic separation, and (c) subjecting said separated glycosyl acceptor and said separated product to fluorescence spectroscopy to quantify the activity of said glycosyltransferase, Montasser et al. teaches the utilization of recombinant human 352 Asn and Ser352 beta-1,4-galactosyltransferase 1 (B4GALT1), where uridine diphosphate galactose (UDP-Gal) and N-acetylglucosamine (GlcNac) are utilized as substrates, wherein the mixture was incubated for 2, 5, 10, 15, 25, 40, and 60 minutes. Further, a hydrophilic interaction liquid chromatography with UV detection and mass spectrometry (HILIC-UV-MS) based method was used to quantify the decrease in UDP-Gal, wherein all samples were analyzed with an Acquity UPLC I-Class coupled with Vion IMS Q-To, and wherein a Waters Acquity UPLC Glycoprotein BEH Amide chromatographic column was used to separate the analytes. Last, the amount of UDP-Gal was quantified by measurement of UV peak areas based on the UV chromatograms and the data were collected and processed using UNIFI software (Supplement, p. 10, “Measuring enzymatic activities using hydrophilic interaction liquid chromatography with UV detection and mass spectrometry (HILIC-UV-MS) analysis”). Regarding claims 4-6, 22-24, and 41, drawn to the enzyme being mutated, naturally occurring, and beta-1,4-galactosyltransferase 1, Montasser et al. teaches the utilization of the wildtype and the mutated Amish enriched missense variant (p.Asn352Ser) beta-1,4-galactosyltransferase 1 (abstract) to determine the levels galactosylation and sialylation of apolipoprotein B100, fibrinogen, immunoglobulin G, and transferrin (abstract). Regarding claims 14-16, 29, 31-34, and 44-46, drawn to the method of detection and subsequent quantification, wherein the mass spectrometry is coupled with liquid chromatography, hydrophilic interaction liquid chromatography, under native conditions, and the said incubated mixture is subjected to ultraviolet detection, Montasser et al. teaches hydrophilic interaction liquid chromatography with UV detection and mass spectrometry (HILIC-UV-MS) based method was used to quantify the decrease in UDP-Gal, wherein all samples were analyzed with an Acquity UPLC I-Class coupled with Vion IMS Q-To, and wherein a Waters Acquity UPLC (Supplement, p. 10, “Measuring enzymatic activities using hydrophilic interaction liquid chromatography with UV detection and mass spectrometry (HILIC-UV-MS) analysis”). Regarding claims 7-9, 25-27, 38, and 43, drawn to the enzyme catalyzing glycosylation, the addition of a sugar molecule onto a protein, and/or the transfer of a functional group onto a protein, the saccharide being galactose, and the donor is uridine diphosphate galactose, Montasser et al. teaches the transfer of galactose from uridine di-phosphate galactose (UDP-Gal) to specific glycoprotein substrates by B4GALT1 (p. 2, Column 1, 1st full paragraph).
Montasser et al. does not teach a labeling substrate in a mixture with donor substrate in a liquid chromatography column (claims 2-3, and 20) where the enzyme contacts the donor substrate before the labeling substrate (claims 17 and 35) or the enzyme contacts the labeling substrate before the donor substrate (claim 18 and 36), wherein the labeling substrate is fluorescent, specifically 2-aminobenzamide (claims 11-12, 30, and 42) capable of binding the sugar molecule of the donor substrate (claims 10 and 28), wherein the labeling substrate is quantified by mass spectrometry (claim 13), wherein 2 or more products are formed over 2 or more incubation times (claim 21), and the glycosyl acceptor is a glycan, specifically a G0F glycan (claims 39-40).
Jung teaches glycans derivatized with 2-aminobenzamide labeling agent and analyzed by HILIC utilizing a Waters high-performance liquid chromatography instrument with a Waters XBridge Amide column (p. 47-48, “Fed-batch culture and glycan anlysis”) to determine the glycan level in the tunable CHO cells molecularly engineered with tunable B4GALT (p. 42 3.3 Discussion), where one of the specific glycans measured in the FUT8-/-- cell line was G0F (p. 34, “Generation FUT8-/- and β4GALT1-/- cells expressing mAb”; p. 36 Fig. 3-2; p. 38 Fig. 3-3). Additionally, multiple products were measured in the samples, i.e. antibodies with fucosylation and/or galactosylation (p. 34, “Generation FUT8-/- and β4GALT1-/- cells expressing mAb”; p. 36 Fig. 3-2; p. 38 Fig. 3-3).
Jung does not teach the reversal of labeling, specifically where the enzyme contacts the labeling substrate before the donor substrate (claim 18 and 36). However, the reversing or changing the order of process steps is obvious unless there is some unexpected result in doing so. See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.) See MPEP 2144.04, Section IV(C).
Therefore, it 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 combine the teachings of Montasser et al. and Jung to utilize a method that fluorescently labels glycans and tests the activity of B4GALT1 because the control of glycosylation profiles is essential for biopharmaceutical production as taught by Jung. One would be motivated to combine these teachings to arrive at the instant claims to investigate variant or wildtype B4GALT1 in cardiovascular disease, such as its role in LDL and fibrinogen formation as taught by Montasser et al (p. 374, Title, 1-3 paragraphs). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Montasser et al. and Jung, since Jung et al. teaches the fluorescent labeling of the glycan donors by a labeling donor and subsequent mass spectrometric measurements of said fluorescent glycans.
Conclusion
22. All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656