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 .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to a method for introducing a payload into an immune cell, in the reply filed on 06/08/2026 is acknowledged.
Applicant’s further election of compound 32 (structure shown below) as the species of ionizable lipid, DOPE as the species of helper lipid, DMG-PEG2000 as the species of stabilizing agent, and mRNA as the species of payload in the reply filed on 06/08/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
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Claims 59-61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/08/2026.
Claims 3-6, 9-11, 14-15, 17, 19-24, 27-28, 30-32, 34, 36-44, and 49-58 are cancelled.
Claims 1-2, 7-8, 12-13, 16, 18, 25-26, 29, 33, 35, and 45-48 are under current examination. The claims were read in view of the species elections detailed above.
Priority
Priority has been claimed to US PRO 63/613,458, filed 12/21/2023, and US PRO 63/477,789, filed 12/29/2022.
Claim Objections
Claim 2 is objected to because of the following informalities: the chemical structure II is blurry; a clear structure should be provided.
Claim 32 is objected to because of the following informalities: it is suggested that “the lipoplex comprises at least one stabilizing agent is selected from…” should read “the lipoplex comprises at least one stabilizing agent.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)-Written Description
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.
Claims 1, 8, 12-13, 16, 18, 25-26, 29, 33, 35, and 45-48 rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims 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, at the time the application was filed, had possession of the claimed invention.
Claim 1 recites: “A method for introducing a payload into an immune cell, comprising: contacting an immune cell with a payload and a lipoplex comprising at least one ionizable lipid compound, thereby introducing the payload into the immune cell; the at least one ionizable lipid compound having the structure I, or pharmaceutically acceptable salts thereof…”. The claims are therefore drawn to a method of contacting an immune cell with a payload and a lipoplex comprising any ionizable lipid compound of the genus of compounds having the structure I or pharmaceutically acceptable salts thereof. However, the instant specification does not describe a representative number of species for the genus of the ionizable lipid compound having the structure I to reasonably convey that Applicant is in possession of the claimed method.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has
been furnished in the disclosure of the Application. These include “level of skill and knowledge in the
art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled
with a known or disclosed correlation between structure and function, and the method of making the
claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the
claimed invention from other materials and would lead one of skill in the art to the conclusion that the
applicant was in possession of the claimed species is sufficient.” MPEP 2163.
Further, for a broad generic claim, the specification must provide adequate written description
to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court
stated:
“A written description of an invention involving a chemical genus, like a description of a
chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical
name,’ of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984
F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85
(CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is
unpredictability in performance of certain species or subcombinations other than those
specifically enumerated, one skilled in the art may be found not to have been placed in
possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d
1398.”
The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus; if the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representatives, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
In the instant case, regarding the genus of isomers of ionizable lipid compounds having the structure I, there are a nearly infinite number of possible combinations of R3, A, Y, X1, R1, B, Z, X2, and R2, and these combinations would be expected have substantial variance in properties such as sterics, solubility, and ability to facilitate cell transfection.
The specification does not set forth a representative number of species by actual reduction
to practice, or by disclosure of relevant, identifying characteristics, or by a combination of such
identifying characteristics, sufficient to show the applicant was in possession of the claimed method of introducing a payload into an immune cell by contacting the cell with a lipoplex comprising the claimed genus to every possible ionizable lipid of structure I (see Eli Lily, 119 F.3d at 1568, 43 USPQ2d
at 1406). The specification exemplifies cell transfections (Examples 1-3 at pgs. 84-88) with formulations containing Compound 32 (see particularly paragraphs [00167] and [00173]) and Compound 43 (see particularly paragraph [00168]).
The MPEP states a "representative number of species" means that the species which are
adequately described are representative of the entire genus. Here, the specification exemplifies immune cell transfection with only two species of ionizable lipid compounds, and therefore does not disclose a representative number of examples to cover the expansive breadth of the genus of ionizable lipid compound having structure I of the claimed method. Accordingly, and in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
In Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, the court clearly states “applicant must convey
with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in
possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever
is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in
the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As stated above, the MPEP states that a broad genus can be described by a showing of
representative number of examples. However, claims 1, 8, 12-13, 16, 18, 25-26, 29, 33, 35, and 45-48 are broad, and the specification does not disclose a representative number of examples which encompass the breadth of the genus of ionizable lipid compounds having the structure I. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.").
Therefore, for these reasons presented above (with emphasis regarding a lack of representative
number of species), the claims lack written description.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-2, 7-8, 12-13, 16, 18, 25-26, 29, 33, 35, and 45-48 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
[AltContent: arrow]The scope of compounds encompassed by structure I is unclear. The recited structure I is reproduced below.
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The claim further defines that the R3 is selected from:
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where “each N* indicates the nitrogen atom N which is explicitly present in the above general structure I to which -A-Y-X1-R1 and -B-(Z-X2)p-R2 are attached”. It is therefore understood by the examiner that each N* corresponds to the nitrogen atom indicated with an arrow in structure I above. There are two N* moieties in each recited R3. However, the claim also recites that X is an integer independently having the value between 1 and 10, inclusively. It is unclear how X can be a value other than 2 (the number of N* moieties of R3). If, for example, X is 10, how are these 10 moieties attached to R3?
The scope of compounds encompassed by structure II in claim 2 is also uncertain. The variable R3 is defined by its relationship to structure I, and its identity in the recited structure II is not defined. For purposes of examination and applying prior art, it is interpreted that the elected species of compound 32 is consistent with an ionizable lipid compound having the structure II.
Claims 8, 12-13, 16, 18, 25-26, 29, 33, 35, and 45-48 are rejected under 35 U.S.C. 112(b) by virtue of their dependency on instant claim 1 and failure to cure the deficiencies noted above.
Claim 7 recites “wherein the at least one ionizable lipid is selected from the group consisting of compounds 1-43” without setting forth the structure of the compounds, rendering the metes and bounds of the claim uncertain. From MPEP 2173.05(s): “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
Claims 46-48 recite the limitation of “a compositional molar ratio”, respectively. It is unclear what is included in the composition forming the basis of the ratio: the lipoplex? the lipoplex + payload? or some other composition? For purposes of examination and applying prior art, the Examiner interprets that the molar ratio is in relation to the lipoplex.
Claim Interpretation
The instant specification states at paragraph [0077] that, “[a]s used herein, the term "lipoplex" is a generic term that includes lipid nanoparticles, liposomes of all types, both unilamellar and multilamellar, as well as vesicles, micelles, exosomes, microvesicles and more amorphous aggregates”. The Examiner thus interprets that lipid nanoparticles, liposomes, vesicles, micelles, exosomes, microvesicles, and amorphous aggregates fall within the scope of the recited “lipoplex comprising at least one ionizable lipid compound”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 7-8, 12-13, 16, 18, 25-26, 29, 33, 35, and 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et. al (US 10,406,237 B2, patented September 10th, 2019), hereafter “Yang” in view of Besin et al. (US 2019/0314291 A1, published October 17th, 2019), hereafter “Besin”.
Regarding instant claim 1-2, 7, and 12-13, Yang teaches amine-containing transfection compounds and transfection complexes made from these compounds; the transfection complexes can encapsulate biologically active agents such as nucleic acids, and can be used in methods of the in vivo or in vitro delivery of the active agents (see entire document, particularly Abstract, and claims 1 and 9). The term “transfection complex” may be thought of as a lipoplex (column 20, lines 38-41). The amine-containing compounds are selected from those including the elected ionizable lipid (see compound 72 at claim 8, reproduced below).
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The transfection complex is taught to include at least one bioactive agent (claims 18-19) of the elected species of mRNA (claim 22). Yang teaches that the transfection complexes may be contacted with the cells to be transfected (column 6, line 64-column 7, line 3; column 112, lines 13-57). The term cell generally refers to eukaryotic cells of any type and from any source (column 18, lines 39-46). The bioactive agent can produce a biological effect such as one that stimulates or causes an immunoreactive response (column 19, lines 43-64).
Regarding instant claim 18, Yang teaches the delivery of transfection agents comprising mRNA that encodes Cre recombinase (column 116, line 61-column 117, line 8). As evidenced by the instant specification, RNA encoding a Cre recombinase is an example of an RNA that encodes a gene editing protein (paragraphs [00100]-[00101]).
Regarding instant claim 25, Yang teaches that the lipids are biodegradable (column 1, lines 33-39) that, when introduced into cells, are broken down into components that the cells can either reuse or dispose of without significant toxic effect (column 19, lines 17-22); thus, it is interpreted that the lipid comprises a biodegradable linkage.
Regarding instant claim 26, as noted above, Yang teaches an ionizable lipid identical in structure to that of the elected species. Per MPEP 2112.01, "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”. Accordingly, the Examiner interprets that the ionizable lipid of Yang meets the limitation of having a protonatable group with a pKa in the range recited in instant claim 26.
Regarding instant claim 29, Yang teaches that the transfection complex comprises at least one helper lipid (claim 12), and the at least one helper lipid is selected from the group including DOPE (claim 15), the elected species of helper lipid.
Regarding instant claim 33, Yang teaches the inclusion of one or more stabilizing agents (column 7, lines 14-24) and the inclusion of one or more pegylated lipids with a PEG polymer having a molecular weight of about 2000 Daltons (column 109, lines 1-44). Suitable lipids can be any lipid compatible with the formation of the transfection complexes (column 109, lines 2-6), and exemplary lipids contemplated for the transfection complexes include DMG (column 4, lines 21-31).
Regarding instant claim 35, Yang teaches that the transfection complexes can include one or more fusogenic or cell-penetrating peptides capable of promoting the fusion of a lipid-containing complex to a cell membrane (column 6, lines 30-40).
Regarding instant claim 45, as noted above, Yang teaches that the transfection complex comprises at least one helper lipid (claim 12), and the at least one helper lipid is selected from the group including DOPE (claim 15), the elected species of helper lipid. Yang further teaches the inclusion of one or more stabilizing agents (column 7, lines 14-24) and the inclusion of one or more pegylated lipids with a PEG polymer having a molecular weight of about 2000 Daltons (column 109, lines 1-44). Suitable lipids can be any lipid compatible with the formation of the transfection complexes (column 109, lines 2-6), and exemplary lipids contemplated for the transfection complexes include DMG (column 4, lines 21-31). Yang teaches that a lipid aggregate can be formed comprising one or more pegylated lipids and optionally one or more helper lipids (column 112, lines 43-57).
Regarding instant claims 46-48, Yang teaches that the molar percentage of the amine-containing transfection compound is from about 15% to about 50% of the lipid aggregate (column 107, lines 7-24), that the molar percentage of the helper lipid is between about 60% and 85% of the lipid aggregate (column 108, lines 61-67), and that the molar percentage of the pegylated lipid is between about 0.5% and 15% of the transfection complex (column 109, lines 45-51). Per MPEP 2144.05 I., “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. Yang further envisions various ratios of amine-containing transfection compound: helper lipid: pegylated lipid, and teaches that optimizing the ratios of such formulations is well within the skill level of such a person, without requiring undue experimentation (column 109, lines 52-67). Per MPEP 2144.05 II. A., “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Yang does not explicitly teach contacting an immune cell (instant claim 1) wherein the immune cell is a T cell, a B cell, natural killer (NK) cell, a dendritic cell, or macrophage (instant claim 8). Yang does not teach that the RNA molecule encodes a chimeric antigen receptor (instant claim 16). Yang does not explicitly teach the elected species of DMG-PEG2000 as the stabilizing agent (instant claims 33, 45, and 48).
Besin teaches immune cell delivery lipid nanoparticle compositions that allow for enhanced delivery of agents (e.g., nucleic acids) to immune cells, and a method of using the nanoparticles for delivery of agents for modulating immune cell activity and modulating immune responses (see entire document, particularly abstract and claims 1 and 63). The method comprises contacting the immune cell with a lipid nanoparticle comprising an ionizable lipid, a helper lipid, and a PEG-lipid (claim 63), and the cell is a T cell, B cell, NK cell, dendritic cell, or macrophage, particularly a T cell (see abstract, paragraph [0005], and claims 65 and 69). Besin further teaches that a T cell response to a cancer antigen can be increased by contacting the T cell with an immune cell delivery nanoparticle and an agent comprising an mRNA encoding a chimeric antigen receptor (claim 67). Besin teaches that in an embodiment, the PEG-lipid is PEG2k-DMG (paragraph [0970]). Ionizable lipids include amine-containing lipids (paragraph [0003]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the method of delivering mRNA active agents to cells of Yang to contact immune cells such as T cells and deliver an mRNA encoding a chimeric antigen receptor, as suggested by Besin. One of ordinary skill in the art would have been motivated to do so in order to engineer immune effector cells to redirect cytotoxicity toward tumor cells (paragraph [0205]-[0206]) and enhance immune recognition and elimination of cancer cells, as suggested by Besin (paragraphs [0061] and [1479]-[1482]). There is a reasonable expectation of success as Besin teaches that mRNA encoding CAR can be delivered via a lipid nanoparticle comprising an ionizable lipid, a helper lipid, and a PEG-lipid, and Yang similarly teaches the delivery of mRNA via transfection complexes comprising amine-containing lipids, one or more helps lipids, and pegylated lipids. Yang further teaches that contacted cells can be of any type (column 18, lines 39-46), and that delivered bioactive agents can produce a biological effect such as one that stimulates or causes an immunoreactive response (column 19, lines 43-64).
It would further have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the pegylated lipid in the transfection complexes of the method of Yang to comprise the DMG-PEG2000 suggested by Besin. One of ordinary skill in the art would have been motivated to do so in order to use an exemplary pegylated lipid that can safely and efficiently deliver biologically active substances in combination with ionizable lipids and helper lipids, as suggested by Besin (paragraphs [0002]-[0005] paragraph [0970]). There is a reasonable expectation of success as Yang teaches the inclusion of one or more pegylated lipids with a PEG polymer having a molecular weight of about 2000 Daltons (column 109, lines 1-44), and that DMG is a suitable lipid for use in the transfection complexes (column 4, lines 21-31).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUDITH M KAMM whose telephone number is (703)756-4575. The examiner can normally be reached M-F 8:00 am-4:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached at (571)272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611
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