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 .
Application Status
Claims 1-5, 9-13, 15, and 17 are pending.
Claims 1-5, 9-13, 15, and 17 are examined on the merits herein.
Priority
The limitation for treatment “with one or more of an RNase, DNase, an enzyme that has DNase and/ or RNase activity, an antibody that binds to an RNA and an antibody that binds to DNA at least two or more times” is not supported in the filing of application 63/170,885, therefore the priority of this claim and the dependent claims 2-17 is 04/05/2022.
Grounds of Rejection Withdrawn
All previous objections and rejections of claims 18-20 are rendered moot by claim cancellation.
Previous objection to claim 11 is withdrawn in view of claim amendment.
Previous rejection of claims 11 under 35 U.S.C. 112(b) is withdrawn in view of claim amendments.
Specification
Objection Maintained
The disclosure is objected to because of the following informalities:
The description of the sequence listing contains a file size listed in kilobytes; the size needs to be in bytes.
Appropriate correction is required.
The use of the term Nanobodies®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Response to Arguments
Applicant's arguments filed December 24, 2025 have been fully considered but they are not persuasive.
There is no amendment to the incorporation of the sequence listing in the instant specification to correct the size description to bytes.
The examiner cannot determine when a term that is trademarked should not include the registered trademark symbol. As the term nanobody® is a registered trademark it is required by the office to include the appropriate symbol. The term nanobody® can be replaced with the terminology: single-domain antibody or VHH to obviate this objection.
Claim Objections
Claims 12 and 17 are objected to because of the following informalities:
Regarding claim 12, monocyte is recited as a cell option twice in line 3, please delete one recitation.
Regarding claim 17, intramuscular is recited as a mode of administration twice in lines 4 and 6, please delete one recitation;
transdermal is recited as a mode of administration twice in lines 6 and 7, please delete one recitation.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
New Rejection Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 12 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 12 recites an option of a CD34+ progenitor cell which is a precursor to white blood cells and can be differentiated into other types of cells that are not white blood cells, for example megakaryocytes, therefore claim 12 is not further limiting to claim 10 from which claim 12 depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
Rejection Maintained
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 9-13, 15, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the 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. This is a scope of enablement rejection.
Nature of the invention/ breadth of the claims.
Claim 1 is drawn to a method of treating infection wherein a white blood cell has been treated at least two times with a DNase, RNase, an enzyme that has DNase or RNase activity, or an antibody that binds to RNA/ DNA to increase the effectiveness of the treated cells to reduce the symptoms of the infection; then administering a therapeutically effectively amount of the cells to the patient; following administration the treated cells reduce the symptoms of the infection.
The issue with the claim as recited is that it is unclear that this method would be effective for a white blood cell to be administered for treatment of symptoms of an any infection and that any RNase or DNase, enzyme that has similar activity or an anti-RNA/ DNA antibody two or more times would be effective.
Claims 2-5 are drawn to specifying/ limiting the type of infection.
Claims 9-12 are drawn to specifying/ limiting the type of cell.
Claim 13, 15, and 17 depend from claim 1 without rectifying the issue identified above.
Further regarding claim 17, claim 17 recites routes of administration for white blood cells including: intracerebral, intracerebroventricular, intraparenchymal injections, intrastriatal, intraspinal, parenteral, subcutaneous, intramuscular, intravenous, intraarterial, inhalation, intradermal, intrathecal, intracisternal magna, epidural and infusion, subarachnoid injection, enteral, oral, intrapleural, transdermal, rectal, nasal, buccal, sublingual, vaginal, intraperitoneal, topical, transdermal administration or inside the site of an infection.
The issue with the claim as recited is that it is unclear that all of these routes of administration would be enabled for a white blood cell to treat an infection; specifically enteral, oral, buccal, sublingual, and topical administration.
State of the prior art/ Predictability of the art.
Kopfnagel (J Invest Dermatol, 2018 Apr, 138(4):872-881; cited in OA 09/25/2025) teaches that RNase7 exhibits potent immunomodulatory functions and supports the efficient recognition of microbial infections by human skin-infiltrating pDC (abstract) and further that RNase 7 functions as an alarmin by converting self-DNA released by dying host cells into a danger signal that activates an antiviral immune response (page 878, col 1, para 2). Kopfnagel further teaches that human pDCs were treated with RNase 7 and human DNA for 6 or 24 hours (methods). Kopfnagel does not teach treating the cells two or more times with RNase alone would increase the effectiveness of the treated cells to reduce the symptoms of an infection.
Tetz (J Leukoc Biol. 2025 Jun 4;117(6):qiaf085; cited in OA 09/25/2025) teaches generation of leucocyte T cells by treating leucocytes and platelets with DNase I and RNase A or with treatment with anti-DNA and anti-RNA antibodies (section 2.3; page 3 col 1, paras 2-3). Tetz further teaches leucocytes secreted proteins associated with immune activation and have direct antimicrobial activity after treatment with RNase A and DNase I in response to LPS stimulation (section 3.1). Although this is not prior art it clearly specifies that the cells used by the inventor are treated with both RNase and DNase like agents, not twice with a single type of agent. There is no prior art demonstrating prior efficacy for enteral, oral, buccal, sublingual, and topical administration of immunotherapy cells.
Guidance in the specification:
The instant specification discloses multiple embodiments that are directed to the treatment of white blood cells with one or more rounds with one or more of a nuclease (including RNase or DNase) or an antibody that binds to an RNA or DNA (para 0285, 0287, and 0289-0292). The instant specification never discloses a particular procedure for the treatment of white blood cells with a particular RNase. DNase or antibody and the number of treatments.
The instant specification discloses that in an embodiment, administration of a treated cell is/are by inhalation, intrapleural, intraabdominal, inhalation, intravaginal, intrarectorally, intramuscular, subcutaneous, intraperitoneal, intraocular, orally, intraventricular, local, and/or intraspinal (para 0262). A treated cell that is to be administered to an individual is administered in a solvent, an emulsion or other diluent in an amount sufficient to maintain the stability of the treated cell prior to and as necessary, following administration (para 0227). In an embodiment, the cells that are treated with one or more of a DNase, an RNase, an anti-RNA antibody and/or anti-DNA antibody in vitro are then administered to a patient in a controlled release formulation. In another embodiment, the controlled release formulation comprise a tablet, a liquid, a powder, a nanoparticle, a controlled release device, subcutaneous autoinjectors. Following administration of the treated cells in a controlled release formulation, the treated cells are released in a controlled release manner (para 0255).
Working examples.
The figures refer to “SL4-C” and “SL4-T” cells which are not defined by the instant specification and it is therefore unclear if these cells are white blood cells. The instant specification teaches that SL4-C and SL4-T cells are derived from whole blood, buffy coats, leukapheresis, Filgrastim, or Plerixafor (para 000324) and derived as previously described (para 000327). The instant specification further teaches that both SL4-C and SL4-T cells were prepared as previously described with DNase, RNase, or antibody treatments (para 000398). In vitro virucidal activity of SL4-T cells was tested (example 16; figure 7) and the in vitro antimicrobial activity was also tested in Table 23-27, Table 33 and example 63. The antimicrobial activity of the SL4-C and SL4-T was tested in vivo in a chick embryo sepsis model (Example 13, Table 28) and mouse sepsis model (example 14; tables 29-30). The efficacy of inhaled immune cells for respiratory infections was also tested in mouse models of pneumonia (example 16; table 31). The efficacy of treated white blood cells and platelets for the treatment of chronic infections (example 17; table 32). The efficacy of treated cells on intracellular parasites was also tested (example 20; Table 35).
Only one of these examples (example 17) does not utilize the SL4-T and SL4-C cells which are not clearly defined herein, therefore the only cell types clearly utilized was white blood cells and platelets. As the SL4 cells were derived from whole blood, buffy coats, leukapheresis, Filgrastim, or Plerixafor this leads to the conclusion that the only viable cells for this type of treatment for infection would be cells present in whole blood and more specifically white blood cells. Further Filgrastim is a medication used to treat neutropenia comprised of granulocyte stimulating factor (G-CSF) and Plerixafor is another medication used to stimulate stem cell mobilization from the bone marrow to the peripheral blood by antagonizing the CXCR4 receptor, so how any cell could be derived therefrom is unclear (Flomenberg, Biol Blood Marrow Transplant. 2010 May;16(5):695-700 and Dale, Support Care Cancer. 2018 Jan;26(1):7-20; cited in OA 09/25/2025).
Example 17 that clearly uses white blood cells and platelets, but merely says treated and untreated, this does not specify what the treatment is or how many times it was applied.
Tables 2, 4, 5, 6-8 in the instant specification disclose immune activity and specifically anticancer activity of immune cells and white blood cells, including different routes of administration including intraperitoneal, intratumoral, subcutaneous, intramuscular, and intravenous. Example 16 further tests inhalation and example 36 further tests rectal administration.
Although the instant specification has clear examples of efficacy with treated white blood cells it is not clearly delineated what treatment was applied. Therefore it is unclear whether any combination of DNase, RNase, anti-RNA antibody or anti-DNA antibody or single agent treatment administered twice.
There are no working examples using enteral, oral, buccal, sublingual, and topical administration of immunotherapy cells.
Amount of experimentation necessary:
As there are no clear examples in the prior art or the instant specification of a white blood cell that is treated with RNase or DNase or a similar single agent twice that increases that cells efficacy in reducing symptoms of an infection. Also, as there are limited examples in the prior art and specification of cell types being treated with an RNase or DNase like agent (whether together, once or more than once) with in vitro or in vivo efficacy against infection it is unclear if this treatment would be effective on all white blood cells and administering to a patient would be effective in treating any type of infection. To test all possible combinations of RNase or DNase type agents two or more times on white blood cells against any type of infection based symptom would require a very extensive amount of experimentation.
Further there is no prior art or examples in the specification using enteral, oral, buccal, sublingual, and topical administration of immunotherapy cells. Establishing a new mode of administration for cellular therapy requires extensive development and validation testing before establishing that it is a valid method.
For the reasons discussed above, it would require undue experimentation for one
skilled in the art to use the claimed methods.
Response to Arguments
Applicant's arguments filed December 24, 2025 have been fully considered but they are not persuasive.
Applicant submits: The specification contains many references to and examples of the efficacy of treated white blood cells. The benefit of the treated white blood cells is further set forth in paragraph 0284, where it is stated that "the improvement further comprises an increased ability to remove, block, kill, adhere to a foreign antigen that resides in the patient." The actual treatment of white blood cells with "a DNase, an RNase, an antibody that binds to a DNA and/or an antibody that binds to an RNA" is set forth in several paragraphs in the specification including, 0285, 0287, 0289, 0290, 0291, 0292 as well as others.
In response: Paragraphs 0285, 0287, 0289, 0290, 0291, and 0292 in the instant specification merely restate that cells are treated with a DNase, an RNase, an antibody that binds to a DNA and/ or an antibody that binds to an RNA; there is no specific combination or multiple iteration of a single agent treatment specified. While various benefits of the treatment are stated in these paragraphs, the treatment itself is not enabled.
There is prior art disclosing treatment with RNase that can increase efficacy of white blood cells in treating an infection, with a specifically detailed treatment protocol. As detailed above, Kopfnagel (J Invest Dermatol, 2018 Apr, 138(4):872-881; cited in OA 09/25/2025) teaches that RNase7 exhibits potent immunomodulatory functions and supports the efficient recognition of microbial infections by human skin-infiltrating pDC (abstract). Kopfnagel further teaches that human pDCs were treated with RNase 7 and human DNA for 6 or 24 hours (methods). Kopfnagel does not teach treating the cells multiple times or use of any other agents besides RNase.
Applicant submits: The pending specification is replete with examples that show the efficacy of white blood cells treated with "a DNase, an RNase, an antibody that binds to a DNA and/or an antibody that binds to an RNA" For instance, Example 1 discloses the use of treated immune cells and shows their increased efficacy at phagocytosis (Table 2). Example 2 shows that treated white blood cells show enhanced anticancer activity against tumor cells (Table 4). In Example 3, Table 5 shows the efficacy of treated white blood cells to reduce spontaneous mammary tumors. Further in Example 3, Table 6 shows that treated white blood cells are shown to have potential applications that require immunomodulation, such as cancer, infections or immune disorders. The ability of the treated white blood cells to function as intended is shown in Table 7, where different routes of administration were tested, with each showing efficacy against tumors (as shown by reduction of tumor size). Similar reduction in tumor size were seen with a pancreatic cancer model (Table 8).
In response: The examples do not specify the steps of the cell treatment including: specifying which agents were used for the treatment or the number of treatments administered to the cells prior to testing. Further the specification refers to SL4-C and SL4-T cells in the examples without defining what these cells are or how they were treated so that the ordinary artisan can properly interpret the results. The instant specification teaches that SL4-C and SL4-T cells are derived from whole blood, buffy coats, leukapheresis, Filgrastim, or Plerixafor (para 000324) and derived as previously described (para 000327). The instant specification further teaches that both SL4-C and SL4-T cells were prepared as previously described with DNase, RNase, or antibody treatments (para 000398).
Example 17 that clearly uses white blood cells and platelets, but merely says treated and untreated, this does not specify what the treatment is or how many times it was applied.
Applicant submits: The point is that the specification is replete with examples showing the efficacy of treated white blood cells. The specification provides sufficient disclosure for the use of treated white blood cells to treat a multitude of diseases.
In Response: While there are numerous examples with SLC-T and some with white blood cells the issue is that these examples are not complete as to the specifics of the treatment of the cells. The specification never details what specific treatment or combination of treatments the cells are subject to before they are tested for efficacy. Would any anti-RNA antibody combined with any RNase result in the same increased efficacy? Or any other combination of options? As anti-RNA/ anti-DNA antibodies function by a different mechanism than RNase/ DNase: essentially antibodies would bind and therefore sequester or block the function of the RNA/DNA and the RNase/ DNase catalyze the degradation of the RNA/ DNA it cannot predicted by the ordinary artisan that these agents would generate the same type of cellular response after ex vivo cellular treatment. Further, what are SL4-T and SL4-C cells?
Conclusion
No claims are allowed.
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 AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643