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 .
Claim Objections
Claims 1-3, 6, 7, 10, and 13 are objected to because of the following informalities:
Regarding claim 1, the definite article ("the") must be added before "C3 position of a sterol skeleton" for reasons of grammar. Given that a sterol skeleton is characterized by a single C3 position, this change does not raise issues of improper antecedent basis.
Regarding claim 2, the lack of a comma preceding the nonrestrictive clause "which…have" is grammatically incorrect. Either "which" must be changed to "that" or a comma must be added.
Regarding claims 2 and 3, "less carbon atoms" must be changed to "fewer carbon atoms."
Regarding claims 2, 3, and 6, the value of an integer must be described as being "fewer" not "less" than a number.
Regarding claim 7, the limitation "the first capture body specifically binding to the tag" is redundant with the following limitation in claim 1: "a first capture body that specifically binds to the tag."
Regarding claim 10, the meaning of the abbreviation "B/F" must be provided the first time the abbreviation appears in the claim set.
Regarding claim 13, the meaning of the abbreviation "ApoAI" must be provided in the claim.
Appropriate correction is required.
Claim Interpretation
Independent claim 1 recites the term "tagged sterol." The IUPAC Gold Book defines "sterols" as "Natural products derived from the steroid skeleton and containing a hydroxy group in the 3 position, closely related to cholestan-3-ol." However, the specification provides the following special definition of "tagged sterol" ([0049] of published application):
The tagged sterol refers to the sterol having a sterol skeleton represented by the above formula, in which a tag is directly or indirectly added to a carbon atom at C3 position thereof.
The reference to "the above formula" in this special definition refers to chemical formula 1 ([0040] of published application), which is reproduced below:
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The claimed term "tagged sterol" is interpreted according to this special definition and is therefore not required to have a hydroxy group at the 3-position of the steroid skeleton, as required by the ordinary and customary meaning of "sterol." Accordingly, claims 2 and 6 are proper dependent claims, despite reciting the tagged sterol is represented by a formula in which a steroid skeleton lacks a hydroxy group at the 3-position.
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.
Claims 1-18 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The claims are generally narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors.
Claim 1 recites the limitation "the tag." There is insufficient antecedent basis for this limitation in the claim. Claims 4 and 7 also recite this limitation.
Claim 1 recites the limitation "forming a complex by contacting: lipoprotein in a sample; a tagged sterol; and a first capture body that specifically binds to the tag and comprises a labeling substance with each other, the complex comprising the lipoprotein comprising the tagged sterol and the first capture body." The punction (colons and semicolons) and italicized limitations are grammatically incorrect and the intended meaning of this limitation is completely unclear. What is "a labeling substance with each other"? Does the first capture body comprise the labeling substance? How can the lipoprotein comprise the tagged sterol and the first capture body when the claim previously sets forth (i) lipoprotein in a sample; (ii) a tagged sterol; and (iii) a first capture body as distinct elements? This is a logical contradiction, and there is insufficient antecedent basis for the limitation "the lipoprotein comprising the tagged sterol and the first capture body."
Claim 1 recites the limitation "the labeling substance comprised in the complex." There is insufficient antecedent basis for this limitation in the claim. From the standpoint of grammar, the most likely antecedent for the previous indefinite limitation "and comprises a labeling substance …" is "a first capture body."
Claim 1 recites the limitation "wherein in the tagged sterol, the tag is added to [the] C3 position of a sterol skeleton." It is unclear whether this is merely a characterization of the tagged sterol or whether this is a step of forming the tagged sterol. Does the method comprise a step of adding a tag to a sterol skeleton?
Claims 2-18 are rejected for depending from indefinite claim 1.
Regarding claim 2, the use of the modal verb "may" is indefinite. For purposes of applying prior art, "which may have" is interpreted as "that optionally have."
Regarding claim 2, the definition of "Z" uses the word "tag" to refer to a subunit of the tagged sterol. This is a different use of the word compared to how it is used in claim 1 ("the tag is added to [the] C3 position of a sterol skeleton"), where the word "tag" apparently refers to a synthetic precursor to the tagged sterol.
Claim 9 recites the limitation "the contact…" in i) and ii). There is insufficient antecedent basis for this limitation in the claim.
Claim 9 recites the limitation "the lipoprotein comprising the tagged sterol." There is insufficient antecedent basis for this limitation in the claim. Claims 10 and 11 also recite this limitation.
Claim 10 recites the limitation "the complex" in ii). There is insufficient antecedent basis for this limitation because both claim 1 and claim 9 previously introduce "a complex."
Claim 14 recites the limitation "the B/F separation." There is insufficient antecedent basis for this limitation in the claim.
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.
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, 5, and 7-18 are rejected under 35 U.S.C. 103 as being unpatentable over Kubo (US 2018/0180607) in view of Hu ("3-Hexanoyl-7-nitrobenz-2-oxa-1,3-diazol-4-yl-cholesterol (3-NBD-cholesterol) is a versatile cholesterol tracer," Steroids 2021).
Regarding claims 1, 5, and 7, Kubo discloses a method for measuring sterol in lipoprotein (Fig. 16B; [0190]-[0201], Example 1, [0217]-[0239]), comprising:
forming a complex (complex 81d, [0198]) by contacting
lipoprotein (target component 80B, which is HDL, [0191], [0222]) in a sample,
a tagged sterol that is tagged cholesterol (capture substance 86a, which is tagged cholesterol, [0196], such as cholesterol having dinitrophenyl group, DNP, as a tag added thereto, [0193]; "DNP-added cholesterol," [0224]), and
a first capture body that specifically binds to the tag ([0198], Fig. 16B) and comprises a labeling substance, the first capture body being a labeled antibody (labeled substance 85, which can be an anti-DNP antibody labeled with ALP, [0198], [0201], [0231]),
with each other,
the complex comprising the lipoprotein comprising the tagged sterol and the first capture body (Fig. 16b; complex 81d, [0198]); and
detecting a signal generated by the labeling substance comprised in the complex (light, [0200], [0201], luminescence, [0233]).
Kubo is silent regarding the attachment position of a tag of the "tagged cholesterol" or the attachment position of the dinitrophenyl (DNP) tag in DNP-added cholesterol. Accordingly, while Kubo discloses that in the tagged sterol, a tag is added to a sterol skeleton, Kubo does not disclose that the tag is added to the C3 position of the sterol skeleton.
In the analogous prior art of using a labeled analog of cholesterol to measure transfer of tagged cholesterol to lipoproteins (abstract; section 3.1), Hu teaches the following regarding the labeling of cholesterol (pages 1-2; reference citations omitted; bolding added):
A wide variety of different fluorescent analogs, including intrinsically fluorescent sterols and modified sterols containing a fluorescent moiety based on 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) or boron-dipyrromethene difluoride (BODIPY), have been used to investigate the distribution and dynamics of cholesterol within cells and membrane. Typically labelling has been achieved on various positions of the isooctyl side chain of cholesterol and 22-NBD-cholesterol, 25-NBD-cholesterol and 24-BODIPY-cholesterol (also known as TopFluor cholesterol) are all widely used to investigate sterol dynamics. However, the introduction of a bulky group on the side chain would be expected to significantly impact properties of the cholesterol and thus the bulk membrane.
[…]
A series of cholesterol analogs incorporating the fluorophore label at the C3-hydroxyl position were prepared by Ramirez and collaborators in 2010. In contrast to the molecules noted above, the NBD fluorophore is attached via an acyl spacer at the C3 position. The orientation of the molecule is similar to that of cholesterol, i.e. the label is located in the polar headgroup region of the membrane and the isooctyl side chain is buried in the membrane core. As initial studies were completed in model membrane systems, we considered it of interest to test the potential of 3-hexanoyl-NBD-cholesterol as a cholesterol tracer for a variety of applications, with a particular interest in its use in relation to measuring uptake of extracellular vesicles.
Hu further teaches the following (end of page 4; reference citations omitted; bolding added):
Although radiolabelled cholesterol is considered to be the gold standard for studies of cholesterol transfer, efforts have been ongoing to identify a fluorescent tracer which would obviate the safety issues related to radioactive cholesterol and also open up new experimental paradigms. As noted above, several different cholesterol tracers are in common use. Typically these are labelled on the side chain of the sterol molecule. This labelling has significant consequences for the physiochemical properties of the molecule. Sterols containing a fluorophore on the side chain (e.g. 22-NBD-cholesterol) transfer between lipophilic compartments orders of magnitude faster than cholesterol itself and have a strongly tilted orientation in the membrane. […] However, the bulky side-chain fluorophore will impact the behaviour of the tracer inside the cell and may lead to erroneous results in the estimation of the ‘exchangeability’ of cholesterol in the cell.
In contrast, as there are no substituents on the side chain 3-NBD-cholesterol would be expected to preserve the orientation of cholesterol in the membrane and more faithfully recapitulate the membrane properties of cholesterol. In agreement with this contention, the flux of cholesterol between erythrocytes and acceptor plasma lipoproteins was near identical to that previously observed for radiolabelled cholesterol.
Accordingly, Hu teaches that a tagged cholesterol having a tag added to the C3 position of the cholesterol skeleton more faithfully recapitulates the membrane properties of cholesterol compared to a tagged cholesterol having a tag added to a side chain position of the cholesterol skeleton.
For the benefit of more faithfully recapitulating the membrane properties of cholesterol, it would have been obvious to one of ordinary skill in the art before the time of filing that in the DNP-added cholesterol of Kubo, the tag is added to the C3 position of the sterol skeleton.
Regarding claim 8, Kubo discloses that in the forming, a second capture body that specifically binds to the lipoprotein (capture substance 86b that reacts with the target component 80B, [0195], which can be an anti-apoA1 antibody, [0196], [0226]) is further used for contacting the lipoprotein, the tagged sterol, and the first capture body ([0197], [0226]).
Regarding claim 9, Kubo discloses that in the forming, the lipoprotein comprising the tagged sterol is contacted with the second capture body ([0197], [0226]), and then a complex (complex 81c, [0197], [0225]) of the lipoprotein comprising the tagged sterol and the second capture body is contacted with the first capture body ([0198], [0231]).
Regarding claim 10, Kubo discloses that in the forming, B/F separation for removing an unreacted free component is performed between
i) the contact between the lipoprotein comprising the tagged sterol and the second capture body and
ii) the contact between the complex and the first capture body ([0197], [0228]).
Regarding claim 11, Kubo discloses that the second capture body is immobilized on a solid phase (magnetic particle 82a, [0195], [0227]) and the complex of the lipoprotein comprising the tagged sterol and the second capture body is formed on the solid phase (Fig. 16b, [0195]).
Regarding claims 12 and 13, Kubo discloses that the second capture body comprises an antibody that specifically binds to the lipoprotein, wherein the antibody that specifically binds to the lipoprotein is an anti-ApoAI antibody ([0196], [0226]).
Regarding claim 14, Kubo discloses that the B/F separation for removing an unreacted free component is performed between the forming and the detecting ([0199], [0232]).
Regarding claim 15, Kubo discloses that the labeling substance is an enzyme and the signal is a chemiluminescent signal generated by contacting the enzyme with a substrate (ALP, [0198], [0201], [0231], [0229], [0233]).
Regarding claim 16, Kubo discloses that the enzyme is alkaline phosphatase (ALP, [0198], [0201], [0231]).
Regarding claim 17, Kubo discloses that the sample is blood, serum, or plasma ([0035], [0077], [0219]).
Regarding claim 18, Kubo discloses that the lipoprotein is high-density lipoprotein ([0191], [0222]).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Kubo in view of Hu as applied to claims 1, 5, and 7-18 above, further in view of Ninomiya (US 2020/0103423).
Regarding claim 4, in the discussion of the capture substance 86a that binds to the labeled substance 85 ([0192]-[0194]), Kubo teaches that the binding between the binding substance and the labeled substance 85 can be from a combination of biotin and avidins ([0193]). Kubo further discloses that the capture substance 86a can be "tagged cholesterol" ([0196], [0201]), without being limited to the example of cholesterol having DNP as a tag ([0194]).
Kubo in view of Hu does not explicitly teach that the tag of the tagged sterol is biotin (and the labeled substance 85 comprises avidin), as opposed to the tag of the tagged sterol being avidin (and the labeled substance 85 comprising biotin). Choosing from a finite number of identified, predictable solutions, with a reasonable expectation for success, is likely to be obvious to a person of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. __,__, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, E.).
In the analogous prior art of measuring uptake of sterol in lipoprotein ([0006]), Ninomiya discloses forming a complex from lipoprotein, a tagged sterol ("labeled sterol," [0026]; "Examples of the tagged sterol include sterols added with…a structure represented by the following formula (III)…"), and a first capture body that specifically binds to the tag ([0030], [0052], [0050]; "Sterol added with a structure represented by the following formula (II) or (III) as a tag is preferable since capture bodies for these tags are generally available," [0053]) and comprises a labeling substance ("Avidin or streptavidin to which a labeling substance such as horseradish peroxidase (HRP) or alkaline phosphatase (ALP) is bound is also commercially available," [0057]).
In a broad embodiment, Ninomiya teaches that "In sterol, a position to which a signal generating substance is added is not particularly limited, and can be appropriately determined according to the type of signal generating substance to be used" ([0064]).
For the benefit of using a known pair of tagged cholesterol and capture body that uses the combination of biotin and avidin, it would have been obvious to one of ordinary skill in the art before the time of filing to use Ninomiya's tagged sterol that is a sterol added with a structure of formula (III) as the tagged cholesterol of Kubo and Ninomiya's commercially available avidin or streptavidin to which a labeling substance such as horseradish peroxidase (HRP) or alkaline phosphatase (ALP) is bound as the capture body of Kubo.
The selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art. See In re Leshin, 125 USPQ 416 (CCPA 1960) (see MPEP § 2144.07).
As set forth above regarding claim 1, Hu teaches that a tagged cholesterol having a tag added to the C3 position of the cholesterol skeleton more faithfully recapitulates the membrane properties of cholesterol compared to a tagged cholesterol having a tag added to a side chain position of the cholesterol skeleton.
For the benefit of more faithfully recapitulating the membrane properties of cholesterol, it would have been obvious to one of ordinary skill in the art before the time of filing that in the Ninomiya's tagged sterol that is a sterol added with a structure of formula (III), the tag is added to the C3 position of the sterol skeleton.
Allowable Subject Matter
Claims 2, 3, and 6 would be allowable if rewritten to overcome the objections and/or rejection(s) under 35 U.S.C. 112(b) and to include all of the limitations of the base claim and any intervening claims.
The prior art of record does not teach or suggest use of a tagged sterol of claim 2 or 6 in the method of claim 1.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHELLE ADAMS whose telephone number is (571)270-5043. The examiner can normally be reached M, T, Th, and F, 12-4 P.M.
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/MICHELLE ADAMS/ Examiner, Art Unit 1797
/JENNIFER WECKER/ Primary Examiner, Art Unit 1797
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