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 .
Priority
This application is a 371 of PCT/US2022/016182 (filed on 2/11/2022), which claims benefit of US provisional 63/193,565 (filed on 5/26/2021), and claims benefit of 63/149,006 (filed on 2/12/2021).
Claims Status
Claims 1,2,4,6,15,17-18,21,23,33,37-38,40,41, and 43 are pending and have been considered on the merits.
Response to Arguments / Status of Rejections
RE: Claim objections of claims 1,2,4, and 18 over minor informalities
Applicants have amended claims 1,2,4 and 18. The amendments to the claims overcomes the basis of the prior objection of record.
The objections are withdrawn.
RE: Rejections of claims 1,2,4,6,15,17,18,21,23,33,41, and 43 under 35 U.S.C. § 103 over Stewart et al (US 2020/0308603 A1) in view of Hansson et al (WO2019/089818 A1), Almarsson et al (WO2020/061295 A1), and Fang et al (International journal of nanomedicine, 2012):
Applicants traverse the rejection on the grounds that a prima facie case of obviousness was not established because there is no reasoning or evidence within Stewart, Hansson, Almarsson, or Fang that would lead the skilled artisan to arrive at the claimed methods using the specific LNP composition of the claims. Applicants also state the substitution of both the amino lipid and the PEG lipid in Stewart et al relies on impermissible hindsight reconstruction of the LNP composition.
These arguments are not found to be persuasive.
This is not found to be persuasive because KSR simple substitution does not require reasoning or evidence for substitution of equivalents. Stewart et al provides teachings of a method for modifying HSPC and is not explicit in the formulation of the amino lipids and the PEG lipid for the method. Hansson, Almarsson, and Fang provide specific options that can be used with LNPs for therapeutic purposes. Therefore, simple substitution established is sufficient for rejection.
Applicants traverse the rejection on the grounds that the cited art does not provide teaching, suggestion, or motivation for the substitutions of the compounds into the method taught by Stewart et al. Applicants state that a broad disclosure of components or combinations is not sufficient to establish why a skilled artisan would select the particular claimed combination.
These arguments are not found to be persuasive.
As stated above, KSR simple substitution does not require teaching, suggestion or motivation for the substitutions of the compounds into the method taught by Stewart et al.
Applicants traverse the rejection on the grounds the modifications made through simple substitution does not establish a reasonable expectation of success in the HSPC context. Applicants state that cited references do not establish a reasonable expectation of success that the substitutions for the amino lipid and PEG lipid into the mRNA-LNP system taught by Stewart et al would produce the claimed result.
These arguments are not found to be persuasive.
As stated above, Stewart et al provides the active steps of the methods and a composition of the LNP used for the method. Substituting known elements in the art for a similar purpose, all references cited, disclose compositions of LNPs, creates an expectation of success. As previously stated in Office action dated 05/04/2026, Stewart et al teaches LNPs with generic lipids or nonspecific formulation, Hansson et al teaches LNPS with compound A (reads on Formula I-I), and Almarsson et al disclosed that high purity PEG lipids with LNPs exhibit superior physical and biological properties and PEG lipid that reads on Formula (I). Therefore, reasonable expectation of success was established, as the method taught by Stewart et al was successful in their embodiments and the lipids that were substituted were successful in their LNP compositions.
Regarding claim 2 Applicants traverse on the grounds that the teachings do not establish the method recited in claim 2; which is drawn to administering the claimed LNP composition to a subject.
This argument is not found to be persuasive.
Stewart et al teaches a method that contacts the LNPs contact HSPCs. Stewart et al disclosed that the cells being engineered or modified reside within a subject tissue or organ, indicating it is in vivo and the LNPs contacting the cells within subject’s tissue or organ requires administering it there.
Therefore, the rejections of claims 1,2,4,6,15,17,18,21,23,33,41, and 43 over Stewart et al (US 2020/0308603 A1) in view of Hansson et al (WO2019/089818 A1), Almarsson et al (WO2020/061295 A1), and Fang et al (International journal of nanomedicine, 2012) are maintained.
RE: Rejections of claims 37-38 under 35 U.S.C. § 103 over Stewart et al (US 2020/0308603 A1), Hansson et al (WO2019/089818 A1), Almarsson et al (WO2020/061295 A1), and Fang et al (International journal of nanomedicine, 2012) in further view of Kauffman et al (Biomaterials, 2016):
Applicants traverse the rejection on the grounds that Kauffman et al does not cure the alleged deficiencies of Stewart et al and other art for independent claim 1. Applicants also state that Kauffman et al does not teach or suggest the presently claimed LNP compositions or provide expectation that adding a chemical modification to mRNA would yield the claimed HSPC modifying method.
These arguments are not found to be persuasive.
As stated the above the deficiencies have been rebutted. Kauffman et al was not relied upon for the composition of the LNP nor the method of the claims. As stated in the Office action dated 05/04/2026, Kauffman et al provides the motivation for the modification of the LNP from Stewart et al, as Kauffman et al teaches that Pseudouridine modified mRNA resist degradation and improved translation efficacy in LNPs (See, p79 col 1). As it would be advantageous to improve the LNPs taught by Stewart et al to resist degradation and improve translation in LNPs, there is teaching, suggestion and motivation for the modification.
Therefore, the rejections of claims 37-38 over Stewart et al (US 2020/0308603 A1), Hansson et al (WO2019/089818 A1), Almarsson et al (WO2020/061295 A1), and Fang et al (International journal of nanomedicine, 2012) in further view of Kauffman et al (Biomaterials, 2016) are maintained.
RE: Rejections of claim 40 under 35 U.S.C. § 103 over Stewart et al (US 2020/0308603 A1), Hansson et al (WO2019/089818 A1), Almarsson et al (WO2020/061295 A1), and Fang et al (International journal of nanomedicine, 2012) in further view of Ramaswamy et al (PNAS, 2017):
Applicants traverse the rejection on the grounds that claim 40 depends on claim 2, and Applicants alleged that claim 2 was not obvious based on the discussion above and Ramaswamy et al does not provide teachings to overcome the alleged deficiencies. Applicants also state that Ramaswamy et al does not provide teaching, suggestions, or reasonable expectation that the claimed LNP composition would modify HSPC in a subject to treat any of the recited disorders.
These arguments are not found to be persuasive.
As stated the above the deficiencies have been rebutted. Ramaswamy et al was not relied upon for the composition of the LNP nor the method of the independent claims. Claim 2 is generic in the disease of disorder. As the method of contacting HSPCs and the LNP had been established in previous rejections, applying the method of treating one of the recited disorders with an LNP was shown. As stated in the Office action dated 05/04/2026, Ramaswamy et al teaches that hemophilia can be treated with an mRNA LNP. While they do not use the mRNA LNP composition recited in the claim or in Stewart et al, it establishes that an mRNA LNP composition is capable of treating the disease.
Therefore, the rejections of claim 40 over Stewart et al (US 2020/0308603 A1), Hansson et al (WO2019/089818 A1), Almarsson et al (WO2020/061295 A1), and Fang et al (International journal of nanomedicine, 2012) in further view of Ramaswamy et al (PNAS, 2017) are maintained.
Claim Interpretation
For clarity, the term “hematopoietic stem and progenitor cell (HSPC)” is defined in the specification as stem and progenitor cells that give rise to other blood cells via a process called hematopoiesis (See Pg 105 of specification). The term “HSPC” encompasses both hematopoietic stem cells (HSC) and hematopoietic progenitor cell (HPC). HSCs are multipotent and capable of self-renewal, and differentiate into progenitor cells which give rise to mature blood cells in the myeloid and lymphoid lineages (See id).
Maintained Grounds of Rejection
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.
Claims 1,2,4,6,15,17,18,21,23,33,41, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Stewart et al (US 2020/0308603 A1) and in view of Hansson et al (WO 2019/089818 A1), Almarsson et al (WO 2020/061295 A1), and Fang et al ( International journal of nanomedicine, 2012).
Stewart et al disclosed a composition and method for introducing an mRNA to stem cells, such as HSPCs (See, Abstract).
Regarding claim 1 and 4, Stewart et al disclosed a method of introducing a genetic change into hematopoietic stem and/ or progenitor cells (HSPC) by contacting HSPC with a lipid nanoparticle (LNP) composition comprising mRNA, an amine lipid, a helper lipid, a neutral lipid and a PEG lipid (See, ¶0005). This reads on a method of modifying a HSPC comprising contacting a cell with LNP composition comprising an mRNA, amino lipid…, a phospholipid…, a structural lipid… and PEG lipid… of the instant claim. Example 1 of Stewart et al, disclosed in their methods that the LNPs are created with a lipid amine, helper lipid, which is cholesterol, neutral lipid, which is DSPC, a PEG lipid, and a GFP mRNA (See, ¶0203). This reads on, …a phospholipid comprising DSPC, a structural lipid comprising cholesterol.
Stewart et al does not disclose the use of the amino lipid comprising a compound of Formula (I-I) nor a phospholipid comprising a compound Formula (VI-D).
Regarding Formula (I-I):
Hansson et al disclosed nanoparticles comprising lipid component and a modified RNA for improving wound healing (See, Abstract)
Hansson et al disclosed two embodiments, embodiment 1 is a nanoparticle comprising a lipid component with compound structure (Compound A), modified RNA encoding VEGF-A polypeptide (See, ¶010) and the second embodiment is the nanoparticle of embodiment 1, wherein the lipid component further comprises phospholipid, structural lipid, and/or a PEG lipid (See, ¶011).
Compound A of Hansson et al reads on Formula (I-I) of instant claim 1 (See, structure p133 of specification (filed on 08/11/2023)).
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Adapted from Hansson et al (WO 2019/089818 A1) (See, ¶010).
Given that both Stewart et al and Hansson et al teach LNPs for contacting cells comprising amino lipids, it would have been prima facie obvious to a person of ordinary skill in the art to substitute the amino lipid in the method of Stewart et al with Compound A of Hansson et al for a similar purpose. Both Stewart et al and Hansson et al teach methods of using LNPs, there would have been a reasonable expectation of success. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered obvious.
This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Regarding Formula (VI-D):
Almarsson et al disclosed the use of high purity PEG lipids with lipid nanoparticle formulations because they exhibit superior physical and biological properties, when it comes delivering therapeutic agents to a subject (See, Abstract).
Almarsson et al disclosed compound of Formula (I) in an embodiment, provided below, such that r = 35-55. (See, ¶0007).
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Adapted from Almarsson (WO 2020/061295 A1) ¶0007
Almarsson et al disclosed that high purity PEG lipids such as Formula (I) have applications in pharmaceutical compositions and drug delivery systems including lipid nanoparticles (LNP) formulations (See, ¶0008).
Almarsson et al disclosed GMP Batch Synthesis of PEG 2000 (Compound I) in figure B (See, ¶00445, Figure B, below). Compound I further limits r = 40-50.
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Adapted from Almarsson (WO 2020/061295 A1) Figure B
Almarsson et al disclosed that those with skill in the art would be able to ascertain with routine experimentation many equivalents to embodiments and be able to modify them without departing from the spirit of the invention.
While Almarsson et al does not disclose the specific use of PEG-45-Stearate, within the art it has been used in the art to improve pharmaceutical drug delivery.
Fang et al teaches solid lipid nanoparticles (SLN) modified with polyethylene glycol (PEG) improves the delivery and localization of PK-L4, a chemotherapeutic (See, Abstract).
Fang et al teaches that the SLN are prepared with PEG monostearate E.O. (45) from Wako Pure Chemical Industries, Ltd (See, Materials p4996 col 2 paragraph 2).
Fang et al teaches that PK-L4 required a suitable carrier and design to overcome the drug delivery to cancer cells. The formulation of a PEGylated SLN successfully encapsulated PK-L4, that allow for distribution from plasma to organs, thus improving localization the delivery system of the therapeutic (See, p5004 col 1 paragraph 5 – col 2 paragraph 1).
Given that both Stewart et al, Almarsson et al, and Fang et al teach LNPs for contacting cells comprising PEG lipids, it would have been prima facie obvious to a person of ordinary skill in the art to substitute the PEG lipid in the method of Stewart et al with Formula (I) of Almarsson et al, with r =45 such as in Fang et al for a similar purpose. Both Stewart et al, Almarsson et al, and Fang et al teach methods of using LNPs for therapeutic or drug delivery, there would have been a reasonable expectation of success. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered obvious.
This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Regarding claim 2, following the discussion above about claim 1, Stewart disclosed that transplantation of HSPCs that contain multipotent HSCs, can be used to treat leukemia, lymphoma, and other disorders (See, ¶0028). Stewart et al further disclosed that in some embodiments the population of cells being engineered with the LNPs reside within a tissue or organ within a subject (See, ¶0187). This reads on, a method of treating.. symptom of a subject having a disease,…. comprising administering [the LNP] to the subject,… thereby treating or ameliorating the symptom of the subject.
Regarding claim 6, Stewart et al disclosed modifying a HSPC or CD34+ cell by contacting HSPC with LNP composition, delivering Cas9 nuclease mRNA and a gRNA in vitro, continuing to culture the cells to have an engineered HSPC (See, ¶0184). Example 1 of Stewart et al, shows the composition of LNP with GFP mRNA (See, ¶0203). Example 2 of Stewart et al shows the LNP with GFP mRNA being contacted with CD34+ cells and the cells then expressing GFP (See, ¶0220-0221). This reads on, comprises modifying a component associated with the cell, … (1) nucleic acid associated with the cell or fragment thereof, (2) peptide or protein associated with the cell…, (ii) the component is endogenous to the cell and/or (iii) component is exogenous to the cell.
Regarding claim 15, following the discussion above, Stewart et al discloses in examples 2 and 4 in vitro methods of contacting cells with LNP compositions (See, ¶0220-0229). This reads on, where in the cell is contacted in vitro.
Regarding claim 17, following the discussion above, Stewart et al disclosed that the HSPC population in the embodiments comprise hematopoietic stem cells and hematopoietic progenitor cells, and have characteristics of being CD34+ (See, ¶0025). Stewart et al does not teach the HSPC being derived from an embryonic stem cell or an iPSC. However, the source of the HSPC is considered a product-by-process limitation. An HSPC is defined by its phenotype, the source does not differentiate the cell. Therefore, an HSPC from any source will still satisfy the physical/biochemical definition of an HSPC. Furthermore, it is noted that Stewart et al teach the HSPCs can be bone marrow or peripheral blood. All cells from a subject (e.g. naturally occurring cells within a subject) are ultimately derived from an embryonic stem cell. Thus, the HSPCs of Stewart et al satisfy the limitation …wherein the HSPC is derived from ES or progenitor cell or an HSPC derived from iPSC…
Regarding claim 18, following the discussion above, Stewart et al disclosed in examples 2 and 4 the use of CD34+ bone marrow cells for contacting of cell to the LNP composition, CD34+ bone marrow cells are multipotent cells, as they can differentiate to red or white blood cells or platelets (See, ¶0220-0229). This reads on, wherein the cell is a multipotent HSC or HPC.
Regarding claim 21, following the discussion above, Stewart et al disclosed method of modifying a HSPC cell. The HSPC are multipotent cells and upon modification in example 7 of Stewart et al, the cells were contacted with LNP delivering Cas9 mRNA and G562 targeting AAVS1. Cell viability was assessed at 3 days and 8 days post contacting with LNP (See, ¶0235). The cell viability is seen in table 3, from day 3 to day 8 there is an increase in the cell viability determined with CountBrightTM absolute counting beads. This indicates the modified cells have proliferative potential. This reads on, wherein the modified HSPC… following functional characteristic…ii. Unlimited proliferative potential. It is also noted that, by definition, HSCs have i. ability to self-renew (as self-renewal is a property of stem cells), iv. ability to differentiate into any hematopoietic lineage, and v. ability to repopulate any hematopoietic lineage (as this is a feature of hematopoietic stem cells).
Regarding claim 23, following the discussion of claim 21 above, the modified HSPC is a hematopoietic stem cell, therefore it inherently has ability to differentiate into any hematopoietic lineage, including myeloid and lymphoid cells. This reads on, wherein the modified HSPC: (i) has the ability to differentiate into myeloid cells; (ii) has the ability to differentiate into lymphoid cells…
Regarding claim 33, following the discussion above, the examples in Stewart et al modified the cell such that it has GFP (Example 2), this modified the cell, but it maintained its expression CD34 (See, ¶0220-0222). This reads on, wherein the modified HSPC has one…. of all of the following expression characteristics:.. (ii) expression of CD34.
Regarding claim 41, following the discussion above about claim 1, the examples 2 and 4 of the LNP contacting cells, there are no additional targeting moiety added to the LNP. This reads on, wherein the LNP does not comprise an additional targeting moiety.
Regarding claim 43, following the discussion above about claim 1, Stewart et al discloses that there are some embodiments where the LNO are formed with pharmaceutically acceptable buffer for in vivo administration of LNPs (See, ¶0181).
Therefore, claims 1,2,4,6,15,17,18,21,23,33,41, and 43 are rendered obvious over Stewart et al in view of Hansson et al, Almarsson et al, and Fang et al.
Claims 37 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Stewart et al (US 2020/0308603 A1), Hansson et al (WO 2019/089818 A1), Almarsson et al (WO 2020/061295 A1), and Fang et al (International journal of nanomedicine, 2012) as applied to claims 1,2,4,6,15,17,18,21,23,33,41, and 43 above, and further in view of Kauffman et al (Biomaterials, 2016) .
The disclosures and teachings of Stewart et al, Hansson et al, Almarsson et al, and Fang et al are set forth above.
Regarding claims 37 and 38, Stewart et al disclosed a method of contacting cells with an mRNA LNP.
Stewart et al does not teach a method wherein the mRNA comprises at least one chemical modification.
Kauffman et al teaches a method of modifying mRNA LNPs with pseudouridine to improve the therapeutic applications (See, Abstract).
Kauffman et al teaches that Pseudouridine modified mRNA resisted ribonuclease (RNase) degradation, reduced activation of Toll like receptors (TLRs) and RNA-dependent protein kinase (PKR), and improved translation efficacy in LNPs (See, p79 col 1). Kauffman et al teaches that the mRNAs were synthesized with or without 100% pseudouridine (PseudoU) and then encapsulated into lipid nanoparticles (LNPs) with methods to optimize mRNA delivery (See, p79 col 2 and Figure 1A). Kauffman et al administered the PseudoU mRNA LNPs in vitro and in vivo; the results indicate that PseudoU mRNA LNPs and controls have similar efficacies when delivered intravenously in mice but had different results in vitro (See, p83 col1-2 Figures 3 and 4).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method disclosed Stewart et al such that the mRNA in the LNP is pseudouridine modified mRNA provided from the method of Kauffman et al. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to make this modification because it would have been advantageous to use PseudoU modified mRNA to protect from degradation and increase translational efficacy of the mRNA in the LNP when contacted with a cell, as taught by Kauffman et al.
Therefore, the mRNA comprises at least one chemical modification of claim 37 and …selected from the group consisting pseudouridine… of claim 38 are rendered obvious over Stewart et al, Hansson et al, Almarsson et al, and Fang et al in view of Kauffman et al.
Therefore, claims 37-38 are rendered obvious over Stewart et al, Hansson et al, Almarsson et al, and Fang et al and in view Kauffman et al.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Stewart et al (US 2020/0308603 A1), Hansson et al (WO 2019/089818 A1), Almarsson et al (WO 2020/061295 A1), and Fang et al (International journal of nanomedicine, 2012) as applied to claims 1,2,4,6,15,17,18,21,23,33,41, and 43 above, and further in view of Ramaswamy et al (PNAS, 2017).
The disclosures and teachings of Stewart et al, Hansson et al, Almarsson et al, and Fang et al are set forth above.
Regarding claim 40, following the discussion of claim 2 above, Stewart et al disclosed a method of contacting cells with and mRNA LNP. Stewart disclosed that transplantation if HSPCs that contain multipotent HSCs, can be used to treat leukemia, lymphoma, and other disorders (See, ¶0028).
Stewart et al does not teach a method wherein the disease or disorder is selected from a group consisting of hemoglobinopathy, a clotting factor disorder…
Ramaswamy et al teaches the use of mRNA LNP to treat Factor IX deficient mouse model of hemophilia B (See, abstract).
Ramaswamy et al teaches that mRNA LNP are an effective way to treat diseases requiring protein replacement, such as hemophilia, a clotting disorder.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method disclosed by Stewart et al such that the disorder being treated with LNP composition is a clotting disorder, as taught by Ramaswamy et al. Both Stewart et al and Ramaswamy et al teach methods of using LNPs, there would have been a reasonable expectation of success, wherein the result of the substitution of the disorders would have been predictable.
Therefore, claim 40 is rendered obvious over Stewart et al, Hansson et al, Almarsson et al, and Fang et al and in view Ramaswamy et al.
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 Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 4:30pm M-Th.
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/CAROLINE M LARA/ Examiner, Art Unit 1633
/ALLISON M FOX/ Primary Examiner, Art Unit 1633
