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 .
Applicant's arguments filed 5-26-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 2-8, 10, 15-20, 27, 30 have been canceled. Claims 1, 9, 11-14, 21-26, 28, 29 are pending.
Election/Restrictions
Applicants elected Group I, claims 1-15, without traverse in the reply filed on 10-25-23. Claims 1, 9, 11-14, 21-26, 28, 29 remain under consideration.
Priority
This application claims benefit of priority from US provisional application No. 62/270,094, filed December 21, 2015. Contrary to the statement in the office action sent 9-5-25, page 1 of the specification correctly identifies the filing date as December 21, 2015.
Claim Objections
Claim 1 can be written more simply to avoid redundancies and ellipses:
The phrase “respective antigens” within the “one or more antibodies and one or more respective antigens” in the preamble of claim 1 is confusing. It is unclear when an antigen is “respective” or to what it is “respective”.
Use of “one or more” twice in the phrase “one or more antibodies and one or more respective antigens” in the preamble of claim 1 is redundant.
The preamble and final step of claim 1 still don’t have a nexus because the preamble requires identifying “one or more antibodies and one or more respective antigens” but the final steps h) and i) require “identifying the one or more antibodies” and “identifying the respective antigen” (singular). The concepts are extremely confusing because the antibodies and antigens were already known and identified as antibodies and antigens when they were put into the system/method. If applicants are attempting to say certain antibodies and antigens were selected from the group based on sequencing results, then the specification fails to teach how to select antibodies or antigens of interest based on their sequences. The phrase “and identifying the respective antigen…” in the phrase “sequencing the nucleic acids from the lysed ASCs and identifying the one or more antibodies” in step h) is a separate step, but it is unclear how any selection occurs as a result of sequencing. The phrase “and identifying the respective antigen…” in the phrase “sequencing the nucleic acid of the (poly)peptide-nucleic acid complex of the captured discplay particles and identifying the respective antigen” in step i) is a separate step, but it is unclear how any selection occurs as a result of sequencing.
The phrase “distributing antibody secreting cells (ASCs) into microfluidic chambers, wherein each of the microfluidic chambers contains a single ASC” in step a) of claim 1 can be written more simply as ---distributing single antibody secreting cells (ASCs)” into microfluidic chambers---.
If there is a culture step between “distributing” in step a) and capturing antibodies in step b) of claim 1, then the culturing step is missing from claim 1.
The meaning of “capturing antibodies secreted by the ASCs on a solid substrate in producing [sic] captured antibodies thereby” in step b) of claim 1 cannot be discerned. Perhaps it is just --- capturing antibodies secreted by the ASCs on a solid substrate---.
If the “solid substrate” in step b) is somehow within the microfluidic chambers (pg 5, para 10), then say that. If the chambers have the “solid substrate” at the beginning of step a), then say that. If the “solid substrate” is in chambers that are different than those used for distributing single ASCs, then say that. If there is an active step of adding a “solid substrate” to the chambers after steps a) and b), then say that.
The container with the “captured antibodies” is exposed to “a plurality of display particles comprising an antigen display library” in step c) of claim 1, but it is unclear when “display particles” have “an antigen display library” or when “an antigen display library” is within the genus of “display particles”. The phrase “antigen display library” has a well-known meaning as a collection of genetically engineered microorganisms (bacteriophages or bacteria) that display a vast diversity of peptides, proteins, or cDNA-encoded antigens. However, the structures/functions associated with a “display particles” comprising “antigen display library”, wherein the “display particles comprise a polypeptide-nucleic acid complex, wherein the polypeptide is an antigen and the nucleic is used to determine the identity of the antigen” cannot be determined. If applicants are simply trying to say the captured antibodies are exposed to an “antigen display library”, then just say that.
If the “antigen display library” in step c) is something more than just microorganisms displaying a vast diversity of antigens, then clearly set the structure out. But since an “antigen display library” was well-known as being limited to microorganisms displaying a vast diversity of antigens, then it is unclear how they can comprise an antigen and a “nucleic acid used to determine the identity of the antigen”. Overall, the structure of a “display particle” comprising an antigen and a “nucleic acid used to determine the identity of the antigen” (and probably a microorganism) cannot be envisioned. Regardless, the structure of each display particle is missing from the claim.
There is no nexus between exposing “captured antibodies” to one or more “display particle” or “an antigen display library” and “sequencing an antibody nucleic acid” because there are no “antibody nucleic acids” associated with the “captured antibodies”.
There is no nexus between exposing “antibody nucleic acid” and an “antigen binding fragment thereof” because the nucleic acid encoding the antibody does not have bind antigens.
The claim set as a whole remains extremely confusing and requires extensive clarification because of redundancies, illogical steps and reagents, typographical and grammatical errors, and general indefiniteness (see 112/2nd below).
Response to arguments
Applicants’ comments are noted but do not adequately address the objections.
Claim Rejections - 35 USC § 112
Written Description
Claims 1, 9, 11-14, 21-26, 28, 29 remain 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.
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Claim 1 is essentially drawn to:
a) distributing single ASC into each of a number of microfluidic chambers;
b) capturing antibodies from the APC obtained in step a) on a substrate in each of the microfluidic chambers;
c) exposing the captured antibodies to a plurality of display particles each comprising an antigen and a nucleic acid used to identify the antigen (and a microorganism) in each of the microfluidic chambers such that display particles bind to the captured antibodies;
d) washing each of the microfluidic chambers obtained in step c) such that unbound display particles are removed; and
e) identifying one or more microfluidic chambers containing a captured antibody bound to a display particle;
f) lysing ASCs present in a microfluidic chamber containing the captured antibody bound to the display particle;
g) sequencing the nucleic acid sequence “used to identify the antigen” in each chamber identified in step f).
The specification lacks written description for any “antibody secreting cell” that produces an antibody as broadly encompassed by claim 1 other than a terminally differentiated B-cell having undergone rearrangement of antibody genes – the B-cell is capable of secreting antibodies. The specification and the art at the time of filing do not teach any other cells that secrete antibodies. Therefore, the breadth lacks written description other than B-cells.
Step a) of claim 1 lacks written description because it requires a sample of “one or more antibody secreting cells (ASCs)” [plural] in a plurality of microfluidic chambers, wherein each chamber “contains a single ASC” [singular]. One ASC cannot be a plurality of cells as claimed. Therefore, the concept lacks written description.
Step c) lacks written description because the specification and the art at the time of filing do not teach when a “plurality of display particles” comprises an “antigen display library”. The container with the “captured antibodies” is exposed to “a plurality of display particles comprising an antigen display library” in step c) of claim 1, but it is unclear when “display particles” have “an antigen display library” or when “an antigen display library” is within the genus of “display particles”. The phrase “antigen display library” has a well-known meaning as a collection of genetically engineered microorganisms (bacteriophages or bacteria) that display a vast diversity of peptides, proteins, or cDNA-encoded antigens. However, the structures/functions associated with a “display particles” comprising “antigen display library”, wherein the “display particles comprise a polypeptide-nucleic acid complex, wherein the polypeptide is an antigen and the nucleic is used to determine the identity of the antigen” cannot be determined. If applicants are simply trying to say the captured antibodies are exposed to an “antigen display library”, then just say that.
If the “antigen display library” in step c) is something more than just microorganisms displaying a vast diversity of antigens, then clearly set the structure out. But since an “antigen display library” was well-known as being limited to microorganisms displaying a vast diversity of antigens, then it is unclear how they can comprise an antigen and a “nucleic acid used to determine the identity of the antigen”.
Most importantly, the specification fails to provide written description for display particles comprising an antigen and a “nucleic acid used to determine the identity of the antigen” (and probably a microorganism). Such a “display particle” cannot be envisioned, is not taught in the specification, and is not taught in the art at the time of filing. At best, pg 25, para 60, contemplates a complex where an antigen is bound to “its nucleic acid coding sequence, or a DNA or RNA that can be used to determined its identity (sometimes referred to as a “barcode” sequence”; however, the specification and the art at the time of filing do not teach how to make any such complex or how to bind an antigen to a “barcode” of its nucleic acid coding sequence. The specification does not teach that an antigen/cDNA “barcode” complex as required in step c) can functionally bind an antibody because the antigen binding site may be blocked by the cDNA “barcode”. Regardless, the specific structure of each display particle is missing from the claim. The microorganism that displays them is missing from the claim. It is unclear how the particle can display both an antigen and a nucleic acid for determining the identity of the antigen. Accordingly, the concept lacks written description.
Step c) also lacks written description for the antibody “interacting” with any portion of any “display particles” as broadly encompassed by step c) other than the antigen displayed on the phage or other organism.
Step d) lacks written description because it never requires capturing an antigen bound to an antibody. If the antigen must be bound to a “barcode”, then the step never requires capturing an antigen/“barcode” complex bound to an antibody. The specification does not teach that an antigen/cDNA “barcode” complex as required in step c) can functionally bind an antibody because the antigen binding site may be blocked by the cDNA “barcode”, so it’s impossible to determine how to capture an antigen/cDNA “barcode” complex functionally bound to an antibody.
Step e) lacks written description because it requires washing “the solid substrate to remove unbound display particles”, but the claim does not require any “solid substrate”, so it’s impossible to determine how to wash it away. Furthermore, the specification fails to teach how to distinguish “display particles” that are bound vs. unbound as claimed, so it’s impossible to determine how to separate them by a “wash”.
Step f) lacks written description because “detecting a signal to identify one or more microfluidic chambers containing at least one of the plurality of captured display particles” because step e) does not require capturing display particles in a microfluidic chamber, adding any detection reagent, or provide any indication of what is being detected, signaled, or selected. It is wholly unclear which “display particles” are being selected or how.
Step g) lacks written description because there is no requirement that the ASCs in one container all have the same genome and encode the same antibodies. Since B-cells with the same genome are capable of antibody gene segment rearrangement, the ASCs in one container all have the same genome and encode the same antibodies because they have different rearrangements of the same genome. It is unclear whether B-cells are cloned before being put into a container. It is unclear whether they are exposed to all peptides of the library or one peptide at a time. It is unclear how to fish out one antibody that binds the peptide within a multitude of captured antibodies in a container. It is unclear how to determine the coding sequence from whence the antibody that binds the peptide came. The specification and figures have been reviewed as best as possible, but there is no place that addresses these discrepancies in the basic concepts contemplated in claim 1. Without such guidance in the specification or the art at the time of filing, step g) of claim 1 does not logically flow and lacks written description.
Step h) lacks written description because there is no way to associate the captured antibody that binds a specific peptide from the library to a nucleic acid sequence encoding the antibody. The specification lacks written description for sequencing nucleic acids encoding antibodies when there are no nucleic acid sequences encoding the antibody associated with the captured antibody that binds peptides from the library.
Similarly, step i) lacks written description because there is no way to sequence nucleic acids encoding antigens when there are no nucleic acid sequences encoding antigens present in the library; they are just antigens. There is no way to determine the nucleic acid sequence encoding the antigen when the antigen is bound to the antibody.
Claims 9, 11-14, 21-26, 28, 29 have been included because they do not clarify the reagents, logic, protocol, or ability to sequence nucleic acids from captured antibodies as claimed. In particular, new independent claim 21 is rejected for reasons set forth in claim 1.
Claim 9 requires expanding the ASCs prior to step a) which is contemplated on pg 17, para 36-37.
The specification lacks written description for performing an antibody affinity or specific assay on ASCs in a microfluidic chamber before exposing them to an antigen display library in the same chamber as encompassed by claim 22 and required in claim 24 or in a different chamber as encompassed by claim 22 and required in claim 25. The concept is contemplated on pg 39, para 111, without providing the protocols and reagents to do so. It is unclear how to take measurements after any reagents are added to the chamber to determine whether the chamber contains ASCs with any desired antibody. The specification and the art do not teach identifying a subpopulation of ASCs of interest by performing an assay while they are in the microfluidic chamber. The specification and the art do not teach identifying a subpopulation of ASCs of interest in a microfluidic chamber by taking them out of the chamber and performing the assay(or putting them back into the microfluidic chamber after the assay). The specification does not teach how to separate any subpopulation of ASCs of interest while they are in the chamber (if that is part of the assay and method). Thus the concept lacks written description.
Claim 23 requires performing an ELISPOT, cytokine neutralization, virus neutralization, or enzyme neutralization assay after distributing ASCs to microfluidic chambers but before capturing antibodies from the ASCs. It is unclear how to take measurements after any reagents for an ELISPOT, cytokine neutralization, virus neutralization, or enzyme neutralization assay are added to the chamber to determine whether the chamber contains ASCs with any desired antibody. The specification and the art do not teach identifying a subpopulation of ASCs of interest by performing an ELISPOT, cytokine neutralization, virus neutralization, or enzyme neutralization assay while they are in the microfluidic chamber. The specification and the art do not teach identifying a subpopulation of ASCs of interest in a microfluidic chamber by taking them out of the chamber and performing the ELISPOT, cytokine neutralization, virus neutralization, or enzyme neutralization assay (or putting them back into the microfluidic chamber after the assay).
Claims 28, 29 require treating cells with Epstein barr virus, CD40L, a toll-like agonist…. for expansion of the ASCs; however, the specification and the art at the time of filing do not teach how such reagents would expand ASCs. Epstein barr virus would kill the cell. A toll-like agonist would cause a heightened state of immune readiness but would not expand the ASCs. Etc. Thus the concept lacks written description.
Response to arguments
Applicants point again to para 24, 28 for ASCs being “ASC precursors, plasma cells, plasmablasts, etc.”. Applicants’ argument is not persuasive because the ASCs must express antibodies in claim 1, and only B-cells express antibodies. “ASC precursors, plasma cells, plasmablasts, etc. do not express antibodies; therefore, the genus lacks written description. Please provide evidence that “ASC precursors, plasma cells, plasmablasts,” etc. secrete antibodies.
Applicants point to para 60, 63-69 for the display particles and say they are “cell-based or cell-free” (pg 9). Applicants’ argument is not persuasive. Everything in the world is either “cell-based or cell-free”, so the statement fails to clarify the metes and bounds of the structures of what applicants consider display particles.
Applicants point to Huang is limited to display particles that are beads coated with various DNA sequences encoding various peptides (pg 9), but the claims are not. The claims require display particles comprising an antigen and a nucleic acid for identifying the antigen, but Huang does not teach this concept. Step 1 of Huang involves DNA templates of some kind on a bedad, but this is not clearly set forth in the claim. Step 2 of Huang involves in vitro transcription/translation of the DNA on the bead which results in the DNA being transcribed and expressed, but this requires streptavidin binding peptide (SBP) which will cause the antigen to “attach to the bead as soon as it is translated resulting [in] the formation of a protein-DNA-bead complex” – this is also not clearly set forth in the claim. Step 3 of Huang requires protein-DNA-bead complexes that bind a protein of interest – this is also not clearly set forth in the claim.
Applicants (again) point to para 81 for step f) (pg 11), but para 81 does not address the issue raised in the rejection. Para 81 discusses using detection reagents to determine which chambers have “display particles” bound to antibodies, but those structures are completely missing from the claim. There are no specific protocols or reagents for distinguishing microfluidic chambers that have antigen/“barcode” cDNA complexes on “display” that are bound to an antibody, especially in a mixed population of ASCs in the chamber as broadly encompassed by claims 1 and 21.
Applicants (again) point to paragraphs 55-56, 121-129 (*pg 11). Applicants’ argument were not and are not persuasive. Paragraphs 55, 56 relate to “functionalized substrate such as functionalized beads”; however, claims 1 or 21 make no such requirement for any “functionalized substrate”. Para 121-129 discuss cytotoxicity, ADCC, cell growth modulation, et al. assays; however, the specification does not teach how to do them in a mixed population of ASCs as broadly encompassed by claim 1. Nor does the specification teach how to do the assays in microfluidic chambers as claimed.
Applicants argue affinity and functional assays for ASCs were well-known, e.g. Ricicova (pg 12). Applicants’ argument is not persuasive. The rejection is based on performing the assays in the microfluidic chamber after exposing the bound antibodies to the display particles, which was not contemplated in the specification.
Applicants’ discussion of “Examiner’s Response to Arguments” on pg 12-14 is noted but fails to address the concerns of the rejection. For example, pg 13, 2nd full para, says the claims are not directed to the manufacture of a display particle that has a DNA-barcoded antigen library attached to it and that doing so was known in the art. If there are “display libraries” with structures other than DNA-barcoded antigens described by Huang, then point them out and describe their structures. There is a sequencing step in claim 1, so the DNA appears to be essential but is missing from the “display particle”.
Enablement
Claims 1, 4, 9-14, 21-29 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 1 and the Examiner’s best guess as to the essence of the claim is described above.
The specification does not enable any “antibody secreting cell” that produces an antibody as broadly encompassed by claim 1 other than a terminally differentiated B-cell having undergone rearrangement of antibody genes – the B-cell is capable of secreting antibodies. The specification and the art at the time of filing do not teach any other cells that secrete antibodies.
Step a) of claim 1 is not enabled because it requires a sample of “one or more antibody secreting cells (ASCs)” [plural] in a plurality of microfluidic chambers, wherein each chamber “contains a single ASC” [singular]. One ASC cannot be a plurality of cells as claimed.
Step c) is not enabled because the specification and the art at the time of filing do not teach when a “plurality of display particles” comprises an “antigen display library”. The container with the “captured antibodies” is exposed to “a plurality of display particles comprising an antigen display library” in step c) of claim 1, but it is unclear when “display particles” have “an antigen display library” or when “an antigen display library” is within the genus of “display particles”. The phrase “antigen display library” has a well-known meaning as a collection of genetically engineered microorganisms (bacteriophages or bacteria) that display a vast diversity of peptides, proteins, or cDNA-encoded antigens. However, the structures/functions associated with a “display particles” comprising “antigen display library”, wherein the “display particles comprise a polypeptide-nucleic acid complex, wherein the polypeptide is an antigen and the nucleic is used to determine the identity of the antigen” cannot be determined. If applicants are simply trying to say the captured antibodies are exposed to an “antigen display library”, then just say that.
If the “antigen display library” in step c) is something more than just microorganisms displaying a vast diversity of antigens, then clearly set the structure out. But since an “antigen display library” was well-known as being limited to microorganisms displaying a vast diversity of antigens, then it is unclear how they can comprise an antigen and a “nucleic acid used to determine the identity of the antigen”.
Most importantly, the specification fails to enable making/using display particles comprising an antigen and a “nucleic acid used to determine the identity of the antigen” (and probably a microorganism). Such a “display particle” cannot be envisioned, is not taught in the specification, and is not taught in the art at the time of filing. At best, pg 25, para 60, contemplates a complex where an antigen is bound to “its nucleic acid coding sequence, or a DNA or RNA that can be used to determined its identity (sometimes referred to as a “barcode” sequence”; however, the specification and the art at the time of filing do not teach how to make any such complex or how to bind an antigen to a “barcode” of its nucleic acid coding sequence. The specification does not teach that an antigen/cDNA “barcode” complex as required in step c) can functionally bind an antibody because the antigen binding site may be blocked by the cDNA “barcode”. Regardless, the specific structure of each display particle is missing from the claim. The microorganism that displays them is missing from the claim. It is unclear how the particle can display both an antigen and a nucleic acid for determining the identity of the antigen.
Step c) is not enabled an antibody “interacting” with any portion of any “display particles” as broadly encompassed by step c) other than the antigen displayed on the phage or other organism.
Step d) is not enabled because it never requires capturing an antigen bound to an antibody. If the antigen must be bound to a “barcode”, then the step never requires capturing an antigen/“barcode” complex bound to an antibody. The specification does not teach that an antigen/cDNA “barcode” complex as required in step c) can functionally bind an antibody because the antigen binding site may be blocked by the cDNA “barcode”, so it’s impossible to determine how to capture an antigen/cDNA “barcode” complex functionally bound to an antibody.
Step e) is not enabled because it requires washing “the solid substrate to remove unbound display particles”, but the claim does not require any “solid substrate”, so it’s impossible to determine how to wash it away. Furthermore, the specification fails to teach how to distinguish “display particles” that are bound vs. unbound as claimed, so it’s impossible to determine how to separate them by a “wash”.
Step f) is not enabled because “identifying one or more microfluidic chambers containing at least one of the plurality of captured display particles” because step e) does not require capturing display particles in a microfluidic chamber.
Step g) is not enabled because there is no requirement that the ASCs in one container all have the same genome and encode the same antibodies. Since B-cells with the same genome are capable of antibody gene segment rearrangement, the ASCs in one container all have the same genome and encode the same antibodies because they have different rearrangements of the same genome. It is unclear whether B-cells are cloned before being put into a container. It is unclear whether they are exposed to all peptides of the library or one peptide at a time. It is unclear how to fish out one antibody that binds the peptide within a multitude of captured antibodies in a container. It is unclear how to determine the coding sequence from whence the antibody that binds the peptide came. The specification and figures have been reviewed as best as possible, but there is no place that addresses these discrepancies in the basic concepts contemplated in claim 1. Without such guidance in the specification or the art at the time of filing, step g) of claim 1 does not logically flow and is not enabled.
Step h) is not enabled because there is no way to associate the captured antibody that binds a specific peptide from the library to a nucleic acid sequence encoding the antibody. The specification does not enable sequencing nucleic acids encoding antibodies when there are no nucleic acid sequences encoding the antibody associated with the captured antibody that binds peptides from the library.
Similarly, step i) is not enabled because there is no way to sequence nucleic acids encoding antigens when there are no nucleic acid sequences encoding antigens present in the library; they are just antigens. There is no way to determine the nucleic acid sequence encoding the antigen when the antigen is bound to the antibody.
Claims 9, 11-14, 21-26, 28, 29 have been included because they do not clarify the reagents, logic, protocol, or ability to sequence nucleic acids from captured antibodies as claimed.
Claim 9 requires expanding the ASCs prior to step a) which is contemplated on pg 17, para 36-37.
The specification does not enable performing an antibody affinity or specific assay on ASCs in a microfluidic chamber before exposing them to an antigen display library in the same chamber as encompassed by claim 22 and required in claim 24 or in a different chamber as encompassed by claim 22 and required in claim 25. The concept is contemplated on pg 39, para 111, without providing the protocols and reagents to do so. It is unclear how to take measurements after any reagents are added to the chamber to determine whether the chamber contains ASCs with any desired antibody. The specification and the art do not teach identifying a subpopulation of ASCs of interest by performing an assay while they are in the microfluidic chamber. The specification and the art do not teach identifying a subpopulation of ASCs of interest in a microfluidic chamber by taking them out of the chamber and performing the assay(or putting them back into the microfluidic chamber after the assay). The specification does not teach how to separate any subpopulation of ASCs of interest while they are in the chamber (if that is part of the assay and method).
Claim 23 requires performing an ELISPOT, cytokine neutralization, virus neutralization, or enzyme neutralization assay after distributing ASCs to microfluidic chambers but before capturing antibodies from the ASCs. It is unclear how to take measurements after any reagents for an ELISPOT, cytokine neutralization, virus neutralization, or enzyme neutralization assay are added to the chamber to determine whether the chamber contains ASCs with any desired antibody. The specification and the art do not teach identifying a subpopulation of ASCs of interest by performing an ELISPOT, cytokine neutralization, virus neutralization, or enzyme neutralization assay while they are in the microfluidic chamber. The specification and the art do not teach identifying a subpopulation of ASCs of interest in a microfluidic chamber by taking them out of the chamber and performing the ELISPOT, cytokine neutralization, virus neutralization, or enzyme neutralization assay (or putting them back into the microfluidic chamber after the assay).
Claims 28, 29 require treating cells with Epstein barr virus, CD40L, a toll-like agonist…. for expansion of the ASCs; however, the specification and the art at the time of filing do not teach how such reagents would expand ASCs. Epstein barr virus would kill the cell. A toll-like agonist would cause a heightened state of immune readiness but would not expand the ASCs. Etc.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to perform the methods of claims 1 and 21 and claims dependent therefrom.
Response to arguments
Applicants’ arguments are the same as those for written description and are not persuasive for reasons set forth above.
Indefiniteness
Claims 1, 9, 11-14, 21-26, 28, 29 remain 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.
Step c) remains indefinite because the specification and the art at the time of filing do not teach when “display particles” contain an “antigen display library”. The container with the “captured antibodies” is exposed to “a plurality of display particles comprising an antigen display library” in step c) of claim 1, but it is unclear when “display particles” have “an antigen display library” or when “an antigen display library” is within the genus of “display particles”. The phrase “antigen display library” has a well-known meaning as a collection of genetically engineered microorganisms (bacteriophages or bacteria) that display a vast diversity of peptides, proteins, or cDNA-encoded antigens. However, the structures/functions associated with a “display particles” comprising “antigen display library”, wherein the “display particles comprise a polypeptide-nucleic acid complex, wherein the polypeptide is an antigen and the nucleic is used to determine the identity of the antigen” cannot be determined. If applicants are simply trying to say the captured antibodies are exposed to an “antigen display library”, then just say that. If the “antigen display library” in step c) is something more than just microorganisms displaying a vast diversity of antigens, then clearly set the structure out. But since an “antigen display library” was well-known as being limited to microorganisms displaying a vast diversity of antigens, then it is unclear how they can comprise an antigen and a “nucleic acid used to determine the identity of the antigen”. Most importantly, the specification fails to provide written description for display particles comprising an antigen and a “nucleic acid used to determine the identity of the antigen” (and probably a microorganism). Such a “display particle” cannot be envisioned, is not taught in the specification, and is not taught in the art at the time of filing. At best, pg 25, para 60, contemplates a complex where an antigen is bound to “its nucleic acid coding sequence, or a DNA or RNA that can be used to determined its identity (sometimes referred to as a “barcode” sequence”; however, the specification and the art at the time of filing do not teach how to make any such complex or how to bind an antigen to a “barcode” of its nucleic acid coding sequence. The specification does not teach that an antigen/cDNA “barcode” complex as required in step c) can functionally bind an antibody because the antigen binding site may be blocked by the cDNA “barcode”. Regardless, the specific structure of each display particle is missing from the claim. The microorganism that displays them is missing from the claim. It is unclear how the particle can display both an antigen and a nucleic acid for determining the identity of the antigen.
Step c) remains indefinite because the metes and bounds of allowing “for the captured antibodies to interact with an antigen present on one or more display particles” encompassed by step c) cannot be determined. The structures/functions associated with the “antibody” “interacting” with a “display particle” or “antigen display library” cannot be determined.
Step d) remains indefinite because it never requires capturing an antigen bound to an antibody. It is unclear whether the antigen must be bound to a “barcode”. If so, then the step never requires capturing an antigen/“barcode” complex bound to an antibody. The specification does not teach that an antigen/cDNA “barcode” complex as required in step c) can functionally bind an antibody because the antigen binding site may be blocked by the cDNA “barcode”. As such, it’s impossible to determine how to capture an antigen/cDNA “barcode” complex functionally bound to an antibody.
Step e) remains indefinite because it requires washing “the solid substrate to remove unbound display particles”, but the claim does not require any “solid substrate”, so it’s impossible to determine how to wash it away. More importantly, it is unclear how to distinguish “display particles” that are bound vs. unbound by “washing” as claimed. So it’s impossible to determine the metes and bounds of how to separate them by a “wash”.
Step f) remains indefinite because “identifying one or more microfluidic chambers containing at least one of the plurality of captured display particles” in step e) does not require capturing display particles in a microfluidic chamber.
Step g) remains indefinite because it is unclear whether the ASCs in one container all have the same genome and encode the same antibodies or if they have different rearranged immunoglobulin genes. Since B-cells with the same genome are capable of antibody gene segment rearrangement, the ASCs in one container all have the same genome and encode the same antibodies because they have different rearrangements of the same genome. But they may not all have the same rearranged immunoglobulin genes. It is unclear whether B-cells are cloned before being put into a container. It is unclear whether they are exposed to all peptides of the library or one peptide at a time. It is unclear how to fish out one antibody for sequencing that binds the peptide within a multitude of captured antibodies in a container. It is unclear how to determine the coding sequence from whence the antibody that binds the peptide came. The specification and figures have been reviewed as best as possible, but there is no place that addresses these discrepancies in the basic concepts contemplated in claim 1. Therefore, step g) of claim 1 does not logically flow and is indefinite.
Step h) remains indefinite because there is no way to associate the captured antibody that binds a specific peptide from the library to a nucleic acid sequence encoding the antibody. Nucleic acids encoding antibodies cannot be sequenced when there are no nucleic acid sequences encoding the antibody associated with the captured antibody (bound to an antigen/“barcode” cDNA complex from the library).
Similarly, step i) remains indefinite because there is no way to sequence nucleic acids encoding antigens when there are no nucleic acid sequences encoding antigens present in the library; they are just antigens. There is no way to determine the nucleic acid sequence encoding the antigen when the antigen is bound to the antibody. This makes the step indefinite.
Claims 9, 11-15, 21-26, 28, 29 have been included because they do not clarify the reagents, logic, protocol, or ability to sequence nucleic acids from captured antibodies as claimed. In particular, new independent claim 21 is rejected for reasons set forth in claim 1.
Claim 15 requires the antigen display library is a phage, yeast, ribosomal, mRNA, or cDNA library but never requires the phage, yeast, ribosomal, mRNA, or cDNA library contains an antigen. This does not make sense because mRNA and cDNA display library do not contain antigens - they’re just mRNA or cDNA on display.
Claim 25 requires antibodies from a functional assay are captured in a different chamber than the one used to perform the functional assay. This is indefinite because the specification does not teach performing a functional assay in the chamber. Nor does it teach capturing antigen/“barcode” cDNA complexes bound to an antibody in a different chamber than the “functional assay”.
Claims 28, 29 require treating cells with Epstein barr virus, CD40L, a toll-like agonist…. for expansion of the ASCs; however, the specification and the art at the time of filing do not teach how such reagents would expand ASCs. Epstein barr virus would kill the cell. A toll-like agonist would cause a heightened state of immune readiness but would not expand the ASCs. Etc. This makes the claims indefinite.
Response to arguments
Applicants discussion of the indefiniteness rejections on pg 15-16 is noted but fails to address any of the issues at hand.
Claim Rejections - 35 USC § 102
Claims 1, 4, 9-14, 21-29 remain rejected under 35 U.S.C. 102a1 as being anticipated by Ricicova (WO 2014153651).
Ricicova cultured and expanded cells that secrete antibodies that bind peptides (pg 4, para 9, 11; pg 8, para 23) by distributing cells that secrete antibodies in a microfluidic chamber (pg 38, para 212, 230). This is equivalent to the “distributing” in claim 1.
Ricicova captured antibodies on a substrate (pg 121, para 416; pg 137, para 464; Fig. 51; pg 163, para 546, Fig. 87; pg 156-157, para 528) as required in claim 1.
Ricicova added an antigen display library to the captured antibodies (pg 66, para 286; pg 45-46, para 235; pg 158-159, para 532-533) as required in step c) of claim 1.
Ricicova identified cells that secrete the antibodies that bind a desired antigen (pg 44, para 230) as required in step d) of claim 1.
Ricicova washed the cells secreting antibodies on pg 63, para 278; pg 121, para 416; pg 170, para 558; pg 182, para 587 as required in claim 1.
Ricicova sequenced nucleic acids encoding antibodies from the identified cells (pg 44-45, para 233; pg 144-148, para 488-497) as required in step e) of claim 1.
Ricicova identified chambers with captured display particles, lysed ASCs in the chamber, and determined whether the cells secreted an antibody against peptide which is a functional assay as well as multiple other ASC functions (pages 64-65, para 282, and page 115, para 398; also page 32, para 198, page 44, para 231, pages 59-60, para 265-266; pg 163, Example 15) as required in steps f) and g) of claim 1.
Ricicova sequenced antigens and antibodies as required in step h) and i) of claim 1 (para 560-562, 570-572, et al.).
Claim 4 has been included because the metes and bounds of “imaging container” are unclear (see 112/2nd) and because Ricicova taught the container is imaged through glass (pg 60, para 269; pg 151, para 507).
Ricicova expanded the cells as required in claim 9 (pg 157, line 3).
Ricicova expanded the subpopulation of clonal cells as required in claim 10 (pg 157, line 3).
Ricicova identified polyclonal antibodies (pg 83, para 344; pg 158, para 532 & 535; claim 35) as required in claim 11.
Claim 12 has been included because the metes and bounds of an “EL4-B5” feeder layer cell line in claim 12 cannot be determined. It is unclear whether any cell line can be named EL4-B5 or if the phrase is limited to a specific cell line or Trade Name. Accordingly, the feeder cells described by Ricicova (pg 86, line 4) are equivalent to the “EL4-B5” feeder layer cell line in claim 12.
Ricicova used a CD40 receptor (pg 57, Table 1, 1st item) which is a CD40 ligand as required in claims 13 and 14.
Claim 21 has been included because steps a), d)-k) of claim 21 are identical to steps a)-i) of claim 1 and because Ricicova determined whether the cells secreted an antibody against peptide which is a functional assay as well as multiple other ASC functions (pages 64-65, para 282, and page 115, para 398; also page 32, para 198, page 44, para 231, pages 59-60, para 265-266; pg 163, Example 15) as required in steps b) and c) of claim 21.
Ricicova determined whether the cells secreted an antibody against specific peptide which is an antibody affinity or antibody specificity assay as required in claim 22.
Ricicova determined whether the cells secreted an antibody against specific peptide using an ELISPOT assay as required in claim 23.
Ricicova taught assaying the antibodies in the same container the capture container (pg 163, Example 15) as required in claim 24 or different container (pg 163, Example 15) than the original chamber (pg 158, last line; Example 6) as required in claim 25.
Response to arguments
Applicants argue Ricicova did not teach or suggest identifying an antibody and an antigen (pg 17). Applicants’ argument is not persuasive because the nucleic acids in step h) encode antigens (not antibodies) and Ricicova sequenced DNA encoding antigens.
Applicants argue Ricicova did not teach exposing antibodies to an antigen display library (pg 17-18). Applicants’ argument is not persuasive. Ricicova added an antigen display library to the captured antibodies (pg 66, para 286; pg 45-46, para 235; pg 158-159, para 532-533) as required in step c) of claim 1.
Applicants argue Ricicova did not capture display particles that interact with antibodies or sequence nucleic acids (pg 20). Applicants’ argument is not persuasive. Ricicova identified cells that secrete the antibodies that bind a desired antigen (pg 44, para 230) as required in step d) of claim 1. Ricicova washed the cells secreting antibodies on pg 63, para 278; pg 121, para 416; pg 170, para 558; pg 182, para 587 as required in claim 1. Ricicova sequenced nucleic acids encoding antibodies from the identified cells (pg 44-45, para 233; pg 144-148, para 488-497) as required in step e) of claim 1. Ricicova identified chambers with captured display particles, lysed ASCs in the chamber, and determined whether the cells secreted an antibody against peptide which is a functional assay as well as multiple other ASC functions (pages 64-65, para 282, and page 115, para 398; also page 32, para 198, page 44, para 231, pages 59-60, para 265-266; pg 163, Example 15) as required in steps f) and g) of claim 1. Ricicova sequenced antigens and antibodies as required in step h) and i) of claim 1 (para 560-562, 570-572, et al.).
Applicants argue Ricicova used beads or cells to which antigens are affixed/expressed, and the identity of the antigen is always known (pg. Applicants’ argument is not persuasive because Ricicova added an antigen display library to the captured antibodies (pg 66, para 286; pg 45-46, para 235; pg 158-159, para 532-533) as required in step c) of claim 1.
Applicants argue those of skill could not make a readout cell with an antigen library displayed on the surface because there would be no way to determine the identity of the antigen. Applicants’ argument is not persuasive because applicants have already acknowledged that one embodiment of Ricicova is using cells expressing various antigens (para 298, “ In a further embodiment, the readout particles are readout cells genetically engineered to express a library of proteins or protein fragments in order to determine the target epitope of the antibody secreted by the effector cells”). Furthermore, the claims encompass display particles that are cells expressing a variety of antigens.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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