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 in the reply filed on 6/22/26 is acknowledged.
Applicant elects, with traverse in part, Annexin V as the binding molecule under Group I. Applicant traverses based on the mischaracterization of phosphatidylethanolamine as one of the claimed binding molecule, when it phosphatidylethanolamine is actually recited as a “cell debris marker” and one binding molecule is an antibody specific for phosphatidylethanolamine.
Examiner agrees that it is an antibody specific for phosphatidylethanolamine that should have been listed as one of the claimed binding molecule in Group I.
Applicant also argues that each alternatives recited in claim are alternative binding systems for carrying out the same method of detecting a cell debris-associated target molecule. Each alternative binds a cell debris marker on cell debris comprising a membrane fragment, thereby producing complexes comprising the binding molecule and cell debris, and the complexes are then used to detect the presence or level of at least one target molecule associated with the complexes. Thus, Applicant argues, the alternatives recited in claim 11 share the same function in the same claimed method, and Applicant submits that the Office has not adequately explained why this common functional relationship fails to link the alternatives or why examination of the generic claims together with claim 11 alternatives would impose a serious search and/or examination burden.
Examiner notes that while the alternatives have a common functional relationship, the alternatives are different biomolecules and as such require different search and consideration, which impose a serious burden. The restriction requirement is considered final, however, rejoinder will be considered throughout prosecution as may be appropriate.
Applicant also elects, without traverse, the species in which the target molecule is PD-L1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 23 and 35 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.
Claim 23 recites in lines 1-3 “the detecting comprises contacting the complexes with at least one binding molecule that binds a target molecule potentially associated with the complexes”. The term “potentially associated” makes the claim unclear since it implies that the target molecule may not be associated with the complex, which contradicts the limitations of detecting the target molecule, which requires that the target molecule be associated with the complex. Examiner suggests that the term “potentially” be deleted to overcome this rejection.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, 4, 7, 11, 15, 16, 20, 23, 25, 30, 36, 42 and 46 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO2015158722 (hereinafter “Mege”).
Applicant’s claim 1 recites:
A method of detecting a cell debris-associated target molecule in a sample, the method comprising:
a) contacting the sample or a subsample thereof with at least one binding molecule, wherein the at least one binding molecule binds a cell debris marker, thereby producing complexes comprising the at least one binding molecule and cell debris, the cell debris comprising a membrane fragment; and
b) detecting the presence or level of at least one target molecule associated with the complexes.
Mege meets the limitations of Applicant’s claim 1 as follows:
a method of detecting a cell debris-associated target molecule in a sample, the method comprising:
contacting the sample or a subsample thereof with at least one binding molecule, wherein the at least one binding molecule binds a cell debris marker, thereby producing complexes comprising the at least one binding molecule and cell debris, the cell debris comprising a membrane fragment
[see Mege on p. 1 disclosing microparticles (MPs) as heterogeneous plasma membrane vesicles bearing proteins and biomarkers of their cells of origin, which are released from different cell types during cell activation activation or apoptosis, and which have been found to play a role in numerous diseases];
[Examiner notes that the MPs disclosed by Mege are equivalent to cell debris recited by Applicant, (see Applicant’s specification in the PreGrant Publication 20240345104 in para. 0096 disclosing: “Cell debris” as used herein means components of dead cells that can be released into the blood or other bodily fluids following apoptosis, autophagic cell death, necrosis, or other types of cell death…” (emphasis added)]
[see Mege on page 22, disclosing measuring microparticles (MPs) in platelet-poor plasma (PPP). The circulating MPs contained in the PPP samples were analyzed using a flow cytometer using beads. The MP cellular origin was detected with a combination of Annexin V and specific antibodies against cells of origin. Fluorescein isothiocyanate-conjugated Annexin V was used to label phosphatidylserine in the MP membrane. For example Annexin V+/CD235+ was used]
[see also Mege on page 23, disclosing MP labeling was based on incubation of patient PPP [platelet-poor plasma] with Annexin V and appropriate antibodies; calcium buffer was then added to improve binding of Annexin V to phosphatidylserine; then paraformaldehyde was added to fix the sample, and beads were added to determine the concentration of MPS]
[Examiner notes that Annexin disclosed by Mege is equivalent to cell debris marker recited by Applicant, (see Applicant’s para. 0094, disclosing “Cell debris marker” as used herein means a molecule, such as a protein, lipid, or carbohydrate, that is physically associated with or embedded in a component of a dead or dying cell and is present in greater proportion in such components of ruptured or intact dead or dying cells than on the outer membrane of intact live cells, intact vesicles, or in the soluble fraction of a sample. The component of the dead or dying cell associated with the cell debris marker may be dissociated from other components of the cell from which it originated or may be contained in an intact dead or dying cell. Examples of cell debris markers include but are not limited to molecules associated with or localized to the inner plasma membrane, e.g., phosphatidylserine and phosphatidylethanolamine…” (emphasis added)]
[see also Mege on p. 26 disclosing determining the concentration of circulating MPs];
and
detecting the presence or level of at least one target molecule associated with the complexes
[see Mege on p. 22-23 disclosing, for example, procoagulant MPs were determined using a combination of brilliant blue-conjugated Annexin V and antibodies identifying procoagulant activity. These procoagulant MPs were determined by the detection of MPs decorated with TF on their surface (defined as Annex V+/TF+) using an Alexa 488-conjugated anti-TF antibody. Tumor MPs were characterized by the detection of MPs expressing tumor markers on their surface using Alexa 647-conjugated anti-Mucinel, etc.]
[see Mege on p. 27 disclosing detecting TF and fibrin on the surface of MPs, as well as the concentration of three glycoprotein tumor markers on the surface of circulating MPs in the plasma of colorectal benign or tumor patients and healthy controls].
As to Applicant’s claims 2 and 4, the plasmas sample in Mege discussed above in claim 1 is a blood sample, as defined by Applicant (see claim 4).
As to claim 7, Annexin V, disclosed by Mege and discussed above regarding claim 1 is a protein.
As to claim 11, the cell debris marker is phosphatidylserine and the binding molecule is Annexin V or an antibody specific for phosphatidylserine;
or the cell debris is phosphatidylethanolamine, and the binding molecule is an antibody specific for phosphatidylethanolamine
[see Applicant’s para. 0094, disclosing “Cell debris marker” as used herein means a molecule, such as a protein, lipid, or carbohydrate, that is physically associated with or embedded in a component of a dead or dying cell and is present in greater proportion in such components of ruptured or intact dead or dying cells than on the outer membrane of intact live cells, intact vesicles, or in the soluble fraction of a sample. The component of the dead or dying cell associated with the cell debris marker may be dissociated from other components of the cell from which it originated or may be contained in an intact dead or dying cell. Examples of cell debris markers include but are not limited to molecules associated with or localized to the inner plasma membrane, e.g., phosphatidylserine and phosphatidylethanolamine…” (emphasis added)].
As to claim 15, the binding molecule [that binds a cell debris marker as recited in claim 1] comprises a label [see Mege page 22 disclosing fluorescein isothiocyanate-conjugated Annexin V] or is conjugated to a solid support [bead, see discussion of claim 1 above].
As to claim 16, Applicant recites that (i) the binding molecule comprises a label, and the method further comprises capturing the binding molecule by binding the label to a solid support;
(ii) the binding molecule is conjugated to a label, wherein the label comprises a fluorophore; and/or
(iii) the solid support comprises a bead.
Mege discloses these limitations, as discussed above regarding claim 1.
For example, see Mege on page 22, disclosing measuring microparticles (MPs) in platelet-poor plasma (PPP). The circulating MPs contained in the PPP samples were analyzed using a flow cytometer using beads. The MP cellular origin was detected with a combination of Annexin V and specific antibodies against cells of origin. Fluorescein isothiocyanate-conjugated Annexin V was used to label phosphatidylserine in the MP membrane. For example Annexin V+/CD235+ was used].
As to claim 20, Applicant recites that the method comprises capturing the complexes from the sample prior to the detecting. Mege discloses this on pages 6-7 which discloses incubating a blood sample with Annexin V, conjugated to a fluorescent label and appropriate specific antibodies, subsequently beads are added, and then the sample is measured using a flow cytometer, wherein the specific antibodies may be, for example, specific antibodies against CD41, CD235a CD lib and fibrin.
As to claim 23, the detecting comprises contacting the complexes with a binding molecule that binds a target molecule associated with the complexes. See, for example, Mege on page 7 disclosing specific antibodies against CD41, CD235a CD lib and fibrin. Examiner notes that such antibodies are binding molecules that bind a target molecule associated with the complexes.
As to claim 25, Mege discloses that the binding molecule that binds a target molecule comprises a label.
See Mege on p. 22-23 disclosing, for example, procoagulant MPs were determined using a combination of brilliant blue-conjugated Annexin V and antibodies identifying procoagulant activity. These procoagulant MPs were determined by the detection of MPs decorated with TF on their surface (defined as Annex V+/TF+) using an Alexa 488-conjugated anti-TF antibody. Tumor MPs were characterized by the detection of MPs expressing tumor markers on their surface using Alexa 647-conjugated anti-Mucinel, etc.]
As to claim 30, the detecting comprises an immunoassay, and optionally, a flow cytometric analysis of complexes.
See Mege on pages 6-7 which discloses incubating a blood sample with Annexin V, conjugated to a fluorescent label and appropriate specific antibodies, subsequently beads are added, and then the sample is measured using a flow cytometer, wherein the specific antibodies may be, for example, specific antibodies against CD41, CD235a CD lib and fibrin.
As to claim 36, the target molecule is a protein. See Mege on page 23 disclosing using anti-TF antibody [as the antibodies identifying procoagulant activity. [TF, understood to be transcription factor, is a protein.] See also Mege on page 7, disclosing use of specific antibodies against CD41, CD235a, CD lib and fibrin. [The targets of, for example, CD41 and fibrin, are proteins.] Examiner notes that the remaining limitations are recited in the alternative.
As to claim 42, see Mege on pages 6-7 which discloses incubating a blood sample with Annexin V, conjugated to a fluorescent label and appropriate specific antibodies, subsequently beads are added, and then the sample is measured using a flow cytometer, wherein the specific antibodies may be, for example, specific antibodies against CD41, CD235a CD lib and fibrin. The targets of these antibodies are considered to be cell type markers.
As to claim 46, Mege teaches measuring total cell debris levels in the sample. See page 5, lines 23-27 disclosing measuring all concentrations of MPs [microparticles]. Examiner notes that the remaining claimed limitations are recited in the alternative.
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.
Claim 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mege (WO 2015158722) in view of Malecki (US 20120093730) and further in view of McKee (US 20190162717).
Mege (discussed above regarding claims 1, 20, 23 and 25), is silent as to the label being an oligonucleotide, and the binding molecule that binds to a cell debris marker comprising an oligonucleotide, and the detecting comprising a proximity ligation assay.
Malecki however Malecki teaches that a cell death marker may be DNA (see para. 0014).
Also, use of nucleic acid labels and ligation assays are known in the art, as shown by McKee (see para. 0076).
Specifically, McKee teaches that in some embodiments, the label is a nucleic acid label. Examples of suitable nucleic acid labels include, but are not limited to, oligonucleotide sequences, single-stranded DNA, double-stranded DNA, RNA (e.g., mRNA or miRNA), or DNA-RNA hybrids. In some cases, the nucleic acid label is an amplified nucleic acid (e.g., by PCR or by isothermal polymerase extension). In some cases, a label or labels are incorporated into a nucleic acid label using a polymerase, reverse transcriptase, ligase, or other enzymes that act on nucleic acids (e.g. fluorescently modified nucleotides, biotin-nucleotides, digoxigenin -nucleotides, hapten nucleotides). In some embodiments, the nucleic acid label is ligated to another label (e.g., a nucleic acid) to create a detectable product (e.g., proximity ligation assays). Para. 0076.
It would have been obvious to one skilled in the art that the Mege invention may be modified such that the target may be an oligonucleotide given that nucleic acids are generally disclosed by Malecki as known cell death markers. Also, it would have been obvious to one skilled in the art that the label used may be an oligonucleotide and the detection the detection method is a ligation assay, as known in the art, as shown by McKee.
Claim(s) 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mege (WO 2015158722) in view of Brown (US 20140220580).
Mege, discussed above, discloses detection of various antibodies.
See, for example, Mege on pages 6-7 which discloses incubating a blood sample with Annexin V, conjugated to a fluorescent label and appropriate specific antibodies, subsequently beads are added, and then the sample is measured using a flow cytometer, wherein the specific antibodies may be, for example, specific antibodies against CD41, CD235a CD lib and fibrin.
However, it is not clear in Mege whether a plurality of target molecules associated with the complexes are detected.
However, Brown discloses that a plurality of targets can be detected, such as by using differently labeled beads for detection with a flow cytometer. Specifically, Brown discloses the following in paragraph 0197.
Flow cytometry can be used in combination with a particle-based or bead based assay. Multiparametric immunoassays or other high throughput detection assays using bead coatings with cognate ligands and reporter molecules with specific activities consistent with high sensitivity automation can be used. For example, beads in each subset can be differentially labeled from another subset. In a particle based assay system, a binding agent or capture agent for a vesicle, such as a capture antibody, can be immobilized on addressable beads or microspheres. Each binding agent for each individual binding assay (such as an immunoassay when the binding agent is an antibody) can be coupled to a distinct type of microsphere (i.e., microbead) and the binding assay reaction takes place on the surface of the microspheres. Microspheres can be distinguished by different labels, for example, a microsphere with a specific capture agent would have a different signaling label as compared to another microsphere with a different capture agent. For example, microspheres can be dyed with discrete fluorescence intensities such that the fluorescence intensity of a microsphere with a specific binding agent is different than that of another microsphere with a different binding agent. Biomarkers bound by different capture agents can be differentially detected using different labels. Para. 0197.
Thus it would have been obvious to one skilled in the art to detect a plurality of different targets with flow cytometry, since this technique is known in the art, as shown by Brown. Also, t would have been obvious that the plurality of targets can be on the same or different complexes [Examiner notes that claim 33 does not specify this aspect, and thus the claim encompasses targets on the same or different complexes.]
Claim(s) 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mege (WO 2015158722).
Claim 35 recites that the method comprises capturing the complexes after contacting the complexes with at least one binding molecule that binds a target molecule associated with the complexes.
Mege shows an embodiment on pages 6-7 in which a blood sample is incubated with Annexin V, conjugated to a fluorescent label and appropriate specific antibodies, subsequently beads are added, and then the sample is measured using a flow cytometer, wherein the specific antibodies may be, for example, specific antibodies against CD41, CD235a CD lib and fibrin.
Thus this example in Mege shows capture of the complex after contacting the complex with a binding molecule that binds a target molecule associated with the complexes.
However, it would have been predictable by one skilled in the art that the same or substantially the same outcome of the assay can result from switching the order of steps such that the method comprises capturing the complexes after contacting the complexes with the binding molecule that binds a target molecule associated with the complex.
Claim 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mege (WO 2015158722) in view of Poma (US 20160177284).
Mege (discussed above regarding claim 1, 33 and 36) is silent as to the target molecule is PD-L1.
However Poma teaches that PD-L1 is programmed death-ligand 1 and is an extraceullular target molecule (that can bind to a binding region of a cell-targeted molecule). See paragraph 0024.
It would have been obvious to one skilled in the art to utilize the teachings of Mege to detect PD-L1 as the target, as may be desirable for study, since Poma teaches that PD-L1 (programmed death-ligand 1) is an extraceullular target molecule (that can bind to a binding region of a cell-targeted molecule).
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Mege (WO 2015158722) in view of Bray (US 20120283954).
Mege discloses using the method to diagnose cancer (see page 5, lines 7-14, for example), and detection of various targets (see page 6, lines 7-13).
However Mege however discloses use of flow cytometer (see for example page 7, line 11), rather than mass spectrometry.
Mass spectrometry however is a well known technique and substitute for other analytical techniques such as flow cytometry, and such is also shown by Bray, for example (see claim 2 of Bray).
It would have been obvious to one skilled in the art to modify Mege to utilize mass spectrometry for analysis of the target proteins.
Conclusion
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/Ann Montgomery/Primary Examiner, Art Unit 1678
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