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 .
This action is in response to the amendment filed 11/24/2025, in which claims 1-21 are currently pending however claims 8, 9 and 15-21 were withdrawn in view of the restriction requirement outlined in the previous Office Action. Claims 1-7 and 10-14 are currently under examination.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Specification
The substitute specification filed 11/24/2025 has been entered as it meets the requirements of 37 CFR 1.125(b) and (c).
Nucleotide and/or Amino Acid Sequence Disclosures
The previous objection has been withdrawn in view of Applicant’s submission of the substitute specification as well as the sequence listing filed 11/24/2025.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1, 2, 4, 6 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over
Claudio et al (US 2008/0063604 Al) in view of Ji et al (US 2004/0028654 Al). This rejection was made in the Office action mailed 07/29/2025.
Regarding claim 1, Claudio teaches a method for ex vivo transduction of biomolecules
from viruses for targeted delivery into target cells [0109]. Claudio teaches non-specific viral
transduction that results from viruses bound non-covalently to the exterior of the microbubble in
such a way that, upon administration, the virus is able to dissociate from the microbubble and
transduce cells [0109]. Claudio teaches microbubbles incorporating such targeting substances
within their shell are included within the scope of the invention such as targeting molecules that
may be included includes: antibodies and antibody fragments, cell adhesion molecules, the
receptors, cytokines, growth factors, peptide hormones, peptide mimetics, and fragments thereof;
non-peptide agonists/antagonists or non-bioactive binders of receptors for cell adhesion
molecules, cytokines, growth factors and peptide hormones; oligonucleotides and modified
oligonucleotides; protease substrates or inhibitors; small molecule ligands of biological
receptors; inactivated proteases wherein the ligands or targeting molecules are biopolymers, and
the methods and compositions of the invention are used in humans, the molecules are preferably
human in origin to reduce the possibility of immunogenicity [0070].
Claudio does not explicitly teach the targeting ligands used for targeting cells as well as
ligands for binding the viruses to the microbubbles.
Ji teaches protamine is a natural, arginine-rich peptide with an overall positive charge
[0013]. Ji teaches methods and compositions of the invention involve a viral composition that
can be administered systemically wherein the invention includes viral compositions having
improved transduction efficiency in vitro, ex vivo, and in vivo and the methods provide for an
increased transduction efficiency and therapeutic efficacy in cancer cells and tumors, in
particular cancer and tumor cells associated with the lung [0012]. Ji teaches the invention
includes viral compositions comprising (a) a protamine molecule and (b) a therapeutic viral vector [0012]. Ji teaches a viral vector and protamine molecule complex can be used for increasing transduction efficiencies, increasing therapeutic efficacy and alleviating side effects of
viral vector therapy, such as neutralizing antibody production and hepatic toxicity [0014]. Ji
teaches the targeting ligand may be operably coupled to a protamine molecule either directly,
e.g. fusion protein, or indirectly by means of linking moiety, for example as a bispecific ligand
including protamine and a targeting peptide [0016]. Ji teaches the targeting moiety is a ligand,
such as a peptide ligand that interacts with cell surface receptors, such as EGFR, VEGFR, and
CAR [0015].
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to modify the teachings of Claudio to include the use of protamine
as a virus specific ligand to bind the viruses to the microbubbles as well as a targeting peptide to
bind to target cell surface receptors such as CAR as taught by Ji because Claudio teaches it is
within the ordinary skill in the art to use a method for ex vivo transduction of biomolecules from
viruses for targeted delivery into target cells where non-specific viral transduction that results
from viruses bound non-covalently to the exterior of the microbubble in such a way that, upon
administration, the virus is able to dissociate from the microbubble and transduce cells and Ji
teaches using protamine in a bispecific targeting ligand such as using protamine to bind a virus
and a targeting peptide to target cell surface receptors such as CAR.
One would have been motivated to make such a modification in order to receive the
expected benefit of improved transduction and targeted delivery to target cells using cell surface
receptor recognition and a protamine ligand for improved transduction of viral particles to a
target cell as taught by Ji.
Regarding claim 2, Claudio teaches wherein the viral vectors are first bound to the microbubbles for concentrating these on the microbubbles before the target cells are introduced
into the mixture for binding subsequently to the microbubbles with the viruses already bound to
the microbubbles [0109].
Regarding claim 4, Claudio teaches bursting the microbubbles after incubation either by
allowing the spontaneous bursting of the microbubbles over time, or applying pressure that is
above an ambient pressure, or by adding a chemical bursting the micro bubbles [0109-0110].
Regarding claim 6, Claudio teaches a method for ex vivo transduction of biomolecules
from viruses for targeted delivery into target cells [0109]. Claudio teaches non-specific viral
transduction that results from viruses bound non-covalently to the exterior of the microbubble in
such a way that, upon administration, the virus is able to dissociate from the microbubble and
transduce cells [0109]. Claudio teaches microbubbles incorporating such targeting substances
within their shell are included within the scope of the invention such as targeting molecules that
may be included includes: antibodies and antibody fragments, cell adhesion molecules, their
receptors, cytokines, growth factors, peptide hormones, peptide mimetics, and fragments thereof;
non-peptide agonists/antagonists or non-bioactive binders of receptors for cell adhesion
molecules, cytokines, growth factors and peptide hormones; oligonucleotides and modified
oligonucleotides; protease substrates or inhibitors; small molecule ligands of biological
receptors; inactivated proteases wherein the ligands or targeting molecules are biopolymers, and
the methods and compositions of the invention are used in humans, the molecules are preferably
human in origin to reduce the possibility of immunogenicity [0070].
Claudio does not explicitly teach the targeting ligands used for targeting cells as well as
ligands for binding the viruses to the microbubbles.
Ji teaches protamine is a natural, arginine-rich peptide with an overall positive charge
[0013]. Ji teaches methods and compositions of the invention involve a viral composition that
can be administered systemically wherein the invention includes viral compositions having
improved transduction efficiency in vitro, ex vivo, and in vivo and the methods provide for an
increased transduction efficiency and therapeutic efficacy in cancer cells and tumors, in
particular cancer and tumor cells associated with the lung [0012]. Ji teaches the invention
includes viral compositions comprising (a) a protamine molecule and (b) a therapeutic viral
vector [0012]. Ji teaches a viral vector and protamine molecule complex can be used for
increasing transduction efficiencies, increasing therapeutic efficacy and alleviating side effects of
viral vector therapy, such as neutralizing antibody production and hepatic toxicity [0014]. Ji
teaches the targeting ligand may be operably coupled to a protamine molecule either directly,
e.g. fusion protein, or indirectly by means of linking moiety, for example as a bispecific ligand
including protamine and a targeting peptide [0016]. Ji teaches the targeting moiety is a ligand,
such as a peptide ligand that interacts with cell surface receptors, such as EGFR, VEGFR, and
CAR [0015].
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to modify the teachings of Claudio to include the use of protamine
as a virus specific ligand to bind the viruses to the microbubbles as well as a targeting peptide to
bind to target cell surface receptors such as CAR as taught by Ji because Claudio teaches it is
within the ordinary skill in the art to use a method for ex vivo transduction of biomolecules from
viruses for targeted delivery into target cells where non-specific viral transduction that results from viruses bound non-covalently to the exterior of the microbubble in such a way that, upon
administration, the virus is able to dissociate from the microbubble and transduce cells and Ji
teaches using protamine in a bispecific targeting ligand such as using protamine to bind a virus
and a targeting peptide to target cell surface receptors such as CAR.
One would have been motivated to make such a modification in order to receive the
expected benefit of improved transduction and targeted delivery to target cells using cell surface
receptor recognition and a protamine ligand for improved transduction of viral particles to a
target cell as taught by Ji.
Regarding claim 10, Claudio teaches the target cells include one of or a combination of T
cells, B cells, tumor-infiltrating lymphocytes, dendritic cells, natural killer cells, endothelial
cells, stem cells and cancer cells from human or animal blood, from other human or animal body
fluids, from human or animal tissues, or from artificial buffer solutions [0117-0120].
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Claudio et al
(US 2008/0063604 Al) in view of Ji et al (US 2004/0028654 Al) as applied to claims 1, 2, 4, 6
and 10 above, and further in view of Wang et al (Biomaterials,183, pgs. 173-184; 2018). This rejection was made in the Office action mailed 07/29/2025.
The teachings of Claudio and Ji are described and applied as above.
Regarding claim 7, Claudio do not teach the target cells are T cells and the viral vectors
are retroviral vectors, and the microbubbles are conjugated with protamine that binds the viral
vectors.
Wang teaches the development of a novel conjugate complex of plectin/integrin-targeted
bispecific molecular probe, termed Gd-Cy7-PTP/RGD (Page 173, Abstract). Wang teaches the bispecific molecular probe comprises four parts: Gd (III) for MRI, cyanine 7 (Cy7) for NIRF, the
peptide PTP for binding to plectin-1 specifically overexpressed on the surface of PDAC cells,
and the peptide RGD for targeting integrin widely expressed on pancreatic duct epithelial cells
and angiogenesis (Page 174, Column 1).
Wang does not teach the use of the bispecific ligand to bind the viral vectors, viruses or
viral-like particles.
Ji teaches Protamine is a natural, arginine-rich peptide with an overall positive charge
[0013]. Ji teaches methods and compositions of the invention involve a viral composition that
can be administered systemically wherein the invention includes viral compositions having
improved transduction efficiency in vitro, ex vivo, and in vivo and the methods provide for an
increased transduction efficiency and therapeutic efficacy in cancer cells and tumors, in
particular cancer and tumor cells associated with the lung [0012]. Ji teaches the invention
includes viral compositions comprising a (a) a protamine molecule and (b) a therapeutic viral
vector [0012]. Ji teaches a viral vector and protamine molecule complex can be used for
increasing transduction efficiencies, increasing therapeutic efficacy and alleviating side effects of
viral vector therapy, such as neutralizing antibody production and hepatic toxicity [0014]. Ji
teaches the targeting ligand may be operably coupled to a protamine molecule either directly,
e.g. fusion protein, or indirectly by means of linking moiety, for example as a bispecific ligand
including protamine and a targeting peptide [0016]. Ji teaches the targeting moiety is a ligand,
such as a peptide ligand that interacts with cell surface receptors, such as EGFR, VEGFR, and
CAR [0015].
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to modify the teachings of Claudio to include the microbubbles are conjugated with a ligand binding to a virus for transduction to a target cell as taught by Ji and the
RGD peptide for specific cell targeting as taught by Wang because Claudio teaches it is within
the ordinary skill in the art to use a method for ex vivo transduction of biomolecules from viruses
for targeted delivery into target cells where non-specific viral transduction that results from
viruses bound non-covalently to the exterior of the microbubble in such a way that, upon
administration, the virus is able to dissociate from the microbubble and transduce cells, Wang
teaches the development of a novel conjugate complex of plectin/integrin-targeted bispecific
molecular probe, termed Gd-Cy7-PTP/RGD and Ji teaches using protamine in a bispecific
targeting ligand such as using protamine to bind a virus and a targeting peptide to target cell
surf ace receptors such as CAR.
One would have been motivated to make such a modification in order to receive the
expected benefit of a protamine ligand for improved transduction of viral particles to a target cell
as taught by Ji and a bispecific ligand utilizing an RGD peptide to bind to target cells as taught
by Wang.
Claims 3, 5, 11, 12, 13 and 14 are rejected under 35 U.S.C. 103 as being
unpatentable over Claudio et al (US 2008/0063604 Al) in view of in view of Ji et al (US
2004/0028654 Al) as applied to claims 1, 2, 4, 6 and 10 above, and further in view of Shi et
al (US 2018/0171295 Al). This rejection was made in the Office action mailed 07/29/2025.
The teachings of Claudio and Ji are described and applied as above.
Regarding claim 5, Claudio and Ji do not teach the original target cell prior to preparing
the mixture is a T-cell and the resulting target cell after incubation is a chimeric antigen receptor
T-cell for use in a CAR-T cell therapy.
Shi teaches method for activating and expanding isolated T cells is created, comprising:
a) adding to isolated T cells ligands presenting microbubbles having a flexible lipid shell with an
inner bubble wall enclosing a gas and an outer bubble wall conjugated to ligands capable of
achieving cell contact dependent juxtacrine signaling on the isolated T cells; and b) adding to
isolated T cells ligands presenting microbubbles having a flexible lipid shell with an inner bubble
wall enclosing a gas and an outer bubble wall conjugated to an antigen capable of forming an
immunological synapse with the T cells [0016]. Shi teaches the use of the invention for CAR-T
cell transduction by recognition of cell surface receptors [0070].
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to modify the teachings of Claudio to include the original target
cell prior to preparing the mixture is a T-cell and the resulting target cell after incubation is a
chimeric antigen receptor T-cell for use in a CAR-T cell therapy as taught by Shi because
Claudio teaches it is within the ordinary skill in the art to use a method for ex vivo transduction
of biomolecules from viruses for targeted delivery into target cells were non-specific viral
transduction that results from viruses bound non-covalently to the exterior of the microbubble in
such a way that, upon administration, the virus is able to dissociate from the microbubble and
transduce cells and Shi teaches the use of microbubbles conjugated with targeting ligands for
CAR-T cell transduction by recognition of cell surface receptors.
One would have been motivated to make such a modification in order to receive the
expected benefit of targeted delivery to T cells for CAR-T therapy as taught by Shi.
Regarding claims 3 and 11, Claudio and Ji do not teach the method comprising:
activating the target cells by adding to the mixture flexible lipid shell microbubbles conjugated to ligands capable of forming an immunological synapse with the target cells or conjugating the
flexible lipid shell microbubbles being conjugated with one or more ligands binding to the
viruses and to the target cells additionally with ligands capable of forming an immunological
synapse with the target cells; and incubating the T cells with the ligands presenting flexible shell
microbubbles over a time span that is sufficient for activating the sparse subset of T cells, the
incubation taking place at least over a part of the incubation time simultaneously with the viral
transduction taking place in the mixture.
Shi teaches a selection strategy that results in a high targeted cell concentration
comprising a mixture of the target cells with the microbubbles (Figure 16; [0034]). Shi teaches
the mixture within the same container comprising the microbubbles, the target cells and the
retroviral vector for targeted binding of the microbubble to the retroviral vector as well as the
target cell [0070].
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to substitute the teachings of Claudio to include the method of
activating the target cells by adding to the mixture nanoparticles conjugated to ligands capable of
forming an immunological synapse with the target cells and incubating the T cells with the
ligands presenting nanoparticles over a time span that is sufficient for activating the sparse subset
of T cells, the incubation taking place at least over a part of the incubation time simultaneously
with the viral transduction taking place in the mixture as taught by Shi because Claudio teaches it
is within the ordinary skill in the art to use a method for ex vivo transduction of biomolecules
from viruses for targeted delivery into target cells where non-specific viral transduction that
results from viruses bound non-covalently to the exterior of the microbubble in such a way that,
upon administration, the virus is able to dissociate from the microbubble and transduce cells and Shi teach a selection strategy that results in a high targeted cell concentration comprising a
mixture of the target cells with the microbubbles and retroviral vector for targeted binding of the
microbubbles to the retroviral vector and target cells.
One would have been motivated to make such a substitution in order to receive the
expected benefit of targeted cell delivery using the method of mixing the microbubbles
conjugated with viruses bound by ligands to deliver biomaterial to the target cell as taught by
Shi.
Regarding claims 12 and 13, Claudio and Ji do not teach the target cells are T-cells and specific T-cell activation is achieved through combining with a unique peptide bound to a recombinant MHC, and anti-CD28 or with other co-stimulating molecules; and nonspecific T cell activation is achieved through combining anti-CD3, and anti-CD28 or with other co-stimulating molecules.
Claudio and Ji do not teach the method comprising achieving at least one of specific and nonspecific T-cell activation through combining with the co-stimulating molecules recombinant CD80 and CD86.
Shi teaches CD3/CD28 affinity ligand combination conjugated microbubbles are infused for the isolation, sorting, expansion, manipulation, or stimulation of T cells (Figures 9-10, [0059]). Shi teaches FIGS. 9-10 demonstrate this preferred embodiment achieving greater cell viability percentages and cell proliferation than solutions used in other embodiments of the present disclosure and in the prior art (Dyna beads) [0059]. This superior outcome may reflect the more natural interaction between microbubbles and T cells to recapitulate immunological synapse [0059]. Shi teaches FIG. 11 demonstrates a preferred embodiment of the present disclosure's microbubble solution (Figure 11; [0060]). Shi teaches the microbubble solution is infused with microbubbles conjugated with CD3/CD28 ligand combination, after cell isolation in a single container has occurred and this anti-CD3/ CD28 microbubble solution can be applied to expand T-cells with greater efficiency and quality than anti-CD3/CD28 Dynabeads, which were developed in the prior art [0060]. Shi teaches the cell expansion profile (CD8/CD4 T cell ratio) is preferred for use in cancer immunotherapy after CD3/CD28 stimulation [0060]. Shi teaches achieving specific T-cell activation through combining with a unique peptide bound to a recombinant MHC, and anti-CD28 or with co-stimulating molecules, such as recombinant CD80 and CD86; and achieving nonspecific T-cell activation through combining antiCD3, and antiCD28 or with co-stimulating molecules, such as recombinant CD80 and CD86 [0107].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Claudio to include the target cells are T cells and specific T-cell activation is achieved through combining with a unique peptide bound to a recombinant MHC, and anti-CD28 or with other co-stimulating molecules; and nonspecific T cell activation is achieved through combining anti-CD3, and anti-CD28 or with other co-stimulating molecules as taught by Shi because Claudio teaches it is within the ordinary skill in the art to use a method for ex vivo transduction of biomolecules from viruses for targeted delivery into target cells where non-specific viral transduction that results from viruses bound non-covalently to the exterior of the microbubble in such a way that, upon administration, the virus is able to dissociate from the microbubble and transduce cells and Shi teaches the target cells are T-cells and specific T-cell activation is achieved through combining with a unique peptide bound to a recombinant MHC, and anti-CD28 or with other co-stimulating molecules; and nonspecific T-cell activation is achieved through combining anti-CD3, and anti-CD28 or with other co-stimulating molecules.
One would have been motivated to make such a modification in order to receive the expected benefit of the specific T-Cell activation by using co-stimulatory molecules as taught by Shi.
Regarding claim 14, Claudio and Ji do not teach the engineered T-cells expressing an anti-CD19 chimeric antigen receptor are adapted for a CAR-T cell therapy for treatment of CD 19+ B cell malignancies.
Shi teaches after washing and resuspending the selected cells in an initiation medium with low IL-2 concentration and two days of culture, the cells and beads were added to culture bags that had been treated with RetroNectin and loaded with anti-CD 19 CAR new culture bags and viral vector and incubated for at least 24 hours [0071]. Shi teaches this transduction step was repeated the day after, and the cells and beads were then transferred to new culture bags and expanded for nine more days [0071]. She teaches the method of any of the preceding embodiments, wherein the sample includes a variety of different cells such as one of or a combination of T cells, B cells, tumor-infiltrating lymphocytes, dendritic cells, natural killer cells, endothelial cells, stem cells and cancer cells from human or animal blood, other human or animal body fluids or artificial buffer solutions [0108].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Claudio to include the teach the engineering T-cells to express an anti-CD19 chimeric antigen receptor that are adapted for a CAR-T cell therapy for treatment in B cell malignancies as taught by Shi because Claudio teaches it is within the ordinary skill in the art to use a method for ex vivo transduction of biomolecules from viruses for targeted delivery into target cells where non-specific viral transduction that results from viruses bound non-covalently to the exterior of the microbubble in such a way that, upon administration, the virus is able to dissociate from the microbubble and transduce cells and Shi teaches beads treated with RetroNectin and loaded with anti-CD 19 CAR new culture bags and viral vector and incubated for at least 24 hours.
One would have been motivated to make such a modification in order to receive the expected benefit of targeted delivery to CAR as taught by Shi.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claims 1, 2, 4, 6 and 10 under 35 U.S.C. 103 as being unpatentable over Claudio et al (US 2008/0063604 Al) in view of Ji et al (US 2004/0028654 Al) has been maintained in view of Applicants arguments filed 11/24/2025. Applicant’s arguments have been fully considered but are not found to be persuasive.
Applicant’s arguments have not been found persuasive because Applicant argues all features in claim 1 are novel over Claudio (US 2008/0063604 A1).
However, claim 1 is rejected as unpatentable over Claudio in view of Ji. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant continues that Claudio does not teach transfer is possible without rupturing the microbubble. Applicant points to a paragraph from Claudio that Applicant argues to support their assertion. However, there is no limitation of the claim requiring transduction of the virus or viral particle without rupturing of the microbubble.
Applicant argues that Claudio does not teach the targeting ligands as well as ligands for binding the viruses to microbubbles. However, this is established in the rejection as Ji teaches this deficiency as stated above.
Applicant argues that Claudio teaches “encapsulation” of a virus within the microbubble but continues that there is no description of how the encapsulation is achieved via incubation. Applicant argues that encapsulation contradicts the present invention as claims as encapsulation means that the encapsulated virus can only escape when the bubble bursts.
However, the current claims do not require or exclude encapsulation within the limitations. Moreover, Claudio teaches that “a virus that is associated with the external surface of a micro bubble is bound non-covalently to the external surface of a microbubble. It is, however, possible that a virus may be partially embedded in the microbubble shell and still be able to infect cells in the absence of micro bubble destruction” [0039]. The Examiner is not relying on any embodiments of Claudio that provide encapsulation.
Applicant argues because Claudio does not teach the specific steps for incubation for encapsulation it also does not meet the limitations of the claims for incubation of the microbubble and the virus or viral particles with the target cells for transduction into a target cell.
However, Claudio teaches microbubbles (including the virus or viral particle, either, encapsulated within the microbubble or bound to the surface of the microbubble) are added to cells, tissue or an organ removed from an organism and sonic energy is applied to rupture the microbubbles to release the virus comprising a viral vector, specifically for ex vivo, the microbubbles comprising the virus or viral particles (either encapsulated or bound to the surface) are incubated with blood or fluid wherein sonic energy is applied and the virus is released and transduces the cells [0113]. The reference does not specify in the particular embodiment whether the virus or viral particle is encapsulated or bound to the outside of the microbubble, therefore, it could be interpreted broadly as bound to the surface of the microbubble.
Applicant’s arguments have not been found persuasive because Applicant argues that Ji (US 2004/0028654 A1) does not teach microbubbles and thus no mechanism that could bind any viral vectors to any microbubbles.
However, claim 1 is rejected as unpatentable over Claudio in view of Ji and therefore the teachings are used in combination to find the instant claims obvious to one of ordinary skill in the art. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant continues to argue that while Ji may teach protamine as nonspecifically binding to a virus it would not have been obvious to the skilled artisan to use such ligand to attach to a microbubble and the instant claims require the microbubbles that are conjugated with one or more ligands which obviously differs from a teaching binding a virus to a virus-specific ligand.
However, the claim limitations are rejected in combination with Claudio as the primary reference and Ji as the secondary reference to teach all the limitations of the claims. As state above, Claudio teaches it is within the ordinary skill in the art to use a method for ex vivo transduction of biomolecules from viruses for targeted delivery into target cells where non-specific viral transduction that results from viruses bound non-covalently to the exterior of the microbubble in such a way that, upon administration, the virus is able to dissociate from the microbubble and transduce cells and Ji teaches using protamine in a bispecific targeting ligand such as using protamine to bind a virus and a targeting peptide to target cell surface receptors such as CAR. Therefore, one would have been motivated to make such a modification in order to receive the expected benefit of improved transduction and targeted delivery to target cells using cell surface receptor recognition and a protamine ligand for improved transduction of viral particles to a target cell as taught by Ji.
Applicant argues that Claudio teaches away from binding viruses non-covalently to the exterior of a microbubble for the purpose of transferring to a target cell, namely teaches “encapsulation” within the microbubble, to deliver the viruses to the target cells by rupturing the microbubbles which is in stark contrast to claiming that the transfer into the target cells is happening while the viruses and the target cells are bound to the microbubbles. Applicant continues to argue that Ji does not fix this deficiency. Applicant continues to point to the same paragraph previously stated ([0109]) arguing that the phrase “without being bound by theory” teaches away by suggesting that the method recited in the paragraph is non-specific and therefore undesirable. Applicant argues that paragraph [0109] is interpreted as inactivating any viruses that are accidently in some unknown fashion non-covalently attached to the exterior of the microbubble which would show Claudio teaching to avoid any transfer of viruses that are non-covalently attached to the microbubble. Applicant insists that Claudio teaches away.
These arguments are not persuasive. The current claims do not require or exclude encapsulation within the limitations. Moreover, Claudio teaches that “a virus that is associated with the external surface of a micro bubble is bound non-covalently to the external surface of a microbubble. It is, however, possible that a virus may be partially embedded in the microbubble shell and still be able to infect cells in the absence of micro bubble destruction” [0039]. The Examiner is not relying on any embodiments of Claudio that provide encapsulation. Applicant has presented an interpretation of the phrase “without being bound by theory” to be interpreted as showing “undesirable” effects, which would be speculative. However, the phrase “without being bound by theory” shows legal terminology for a lack of limitation to the single theory being established within that single embodiment. By interpreting the previous phrase as such the following arguments are not persuasive that Claudio teaches away.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637