DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-6, 10, 12-15, 18, 20-22, 24, 28-29 and 31-32 are pending.
Election/Restrictions
Applicants’ election of Group I, claims 1-6, 10, 24 and 28, in the reply filed on 8/24/26 is acknowledged. There is no indication of whether the election is with or without traverse, but because the response 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 § 818.03(a)). Claims 12-15, 18, 20-22, 29 and 31-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The elections of (1) PECAM-1 as the species of cell surface target of a targeting moiety, and (2) rheumatoid arthritis as the species of inflammatory or autoimmune disease or disorder, are also acknowledged. Each elected species reads on each claim in the elected group.
Claims 1-6, 10, 24 and 28 are under consideration.
Specification
The disclosure is objected to because of the following informalities:
---At page 76, line 10, “Sheilding” should be “Shielding”.
Appropriate correction is required.
Claim Objections
Claim 2 is objected to because of the following informalities:
In claim 2, “poly glutamic acid” should be “polyglutamic acid”.
Appropriate correction is required.
Improper Markush Grouping Rejection
Claims 2 and 3 rejected on the basis that each contains or encompasses an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the group (i.e., alternatives from which a selection is to be made) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, that do not belong to a recognized class, the members of the grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the feature. See MPEP § 706.03(y).
In claim 2, the Markush grouping of CD47 polypeptide, SIRPα activator, PD-L1 polypeptide, PD-1 activator, CD24 polypeptide, Siglec-10 activator, polyglutamic acid peptide, β2M polypeptide, and LILRB1 activator is improper for the following reasons. The moieties, all polypeptides or activators of polypeptides, do not belong to an art-recognized class. Second, while the polypeptides (or activators of polypeptides) share a common use as a delivery vehicle, they do not share a structural similarity. Each polypeptide has a different amino acid sequence that results in a different molecular structure that forms the basis for its activity. Furthermore, each “activator” encompasses a genus of different molecules (proteins, antibodies, small organic molecules) having different structures. Claim 3 is included in this rejection because it depends from claim 2 and encompasses the same Markush type group.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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.
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 1-6, 10 and 24 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Per MPEP 2163, 35 U.S.C. 112(a) requires, “separate and distinct from the enablement requirement”, that the “specification shall contain a written description of the invention…” (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The invention of independent claim 1 is a product; specifically, a composition comprising a therapeutic agent and a delivery vehicle that comprises a moiety to inhibit uptake of the composition by a macrophage. The elected invention under consideration is where the delivery vehicle comprises a CD47 polypeptide or an active fragment thereof, which is recited in the alternative in dependent claim 2. Claim 3 further limits the CD47 polypeptide. Claims 4-6 and 10 depend from claim 1 and limit other aspects of the product. Claim 24 is an independent claim directed to an embodiment that is limited to an active CD47 polypeptide, and dependent claim 25 further limits the CD47 polypeptide.
In a review of the prior art, Kaur et al (2021) teaches that CD47 is a protein of 323 (long isoform) or 305 (short isoform) amino acids (page 3 of Kaur et al, 2021 October 26. Atlas Genet Cytogenet Oncol Haematol. Author manuscript; pages 1-38). Kaur further teaches that the extracellular domain of with its counter-receptor signal regulatory protein-α” (SIRPα) on the surface of certain cell types, including macrophages, and that “CD47-induced SIRPA signaling in macrophages plays a role in limiting phagocytosis of RBCs, stem cells, and tumor cells” (page 5). The prior art further recognizes that a “self-peptide” of 21 amino acids derived from the extracellular domain CD47 can provide the functionality with respect to reduction of phagocytosis by macrophage (see page 219 of Huang et al, February 2021, Nature Nanotechnology. 16: 214-223 plus supplementary materials; 18 pages total).
The term “polypeptide” is defined by the instant specification as including “biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others” (¶ 77, published application). Thus, the term “CD47 polypeptide” as recited in dependent claim 2 and encompassed by claim 1 encompasses a genus of variants of the wild type CD47 protein, including variants of the 21 amino acids that are recognized as conferring the required functionality. This genus includes hundreds possible combinations of mutations in the 21 amino acids of the self-peptide. Furthermore, the claims also encompass “active CD47 polypeptide fragments”, and the term “active” is not defined by the specification but presumably refers to a fragment that retains the activity required by the moiety, i.e., “inhibiting uptake of the composition by a macrophage”. As such, the elected invention also encompasses fragments of CD47 and variants thereof that retain its functionality. Such fragments include the self-peptide but also fragments of CD47 comprising less than the entirety of the self-peptide.
With respect to mutated variants of proteins, the prior art appreciates that "Mutations … are generally destabilizing, and can reduce protein … fitness" and "In general, more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation" (pg 602 of Tokuriki et al, 2009, Current Opinion in Structural Biology. 19: 596-604). The prior art also appreciates that "the range of possible SNV [single nucleotide variation] effects at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge" (pg 18 of Bhattacharya et al, 2017. Plos One. 12(3): e0171355, pages 1-22 as printed). Thus, knowledge of the sequence of a protein (e.g., the CD47 self-peptide) is not alone sufficient for the skilled artisan at the time of the effective filing date to predict which mutations (substitutions, additions and/or deletions) in the protein can be made and still retain the required functionality.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[A] sufficient description of a genus … requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
Per MPEP 2163, "A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")
In the instant case, the specification provides limited guidance as to the nature of which members of the large genus of CD47 polypeptide variants will have the required functionality (i.e., inhibiting uptake of the composition of a macrophage). At page 123, the specification teaches two peptides derived from CD47 that were used for the experiments described in the working examples. Each peptide is 24 amino acids in length. In SEQ ID NO: 2, residues 4-24 correspond to the 21 amino acids of the “self-peptide” derived from human CD47 that was known in the prior art (e.g., Huang et al, 2021, cited above). Residues 4-24 of SEQ ID NO: 1 instead correspond to the same region of the murine CD47 polypeptide. Each sequence has three additional residues as the N-terminus: a lysine at residue 1 with an azide (N3) modification, and a glycine at residues 2 and 3. However, a description of only two species having the required activity is not representative of a claimed genus of CD47 polypeptide variants and fragments because it does not identify which of the hundreds of variants and/or fragments of the self-peptide will have the required activity (inhibiting uptake of the composition by a macrophage).
The specification does not provide sufficient description to identify a representative number of species encompassed by the claimed genus by any method other than screening for additional members. However, as with antibodies, adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), 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” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
Furthermore, the claims also lack a written description of the broader genus of “a moiety to inhibit uptake of the composition of macrophage”. Beyond CD47, such a genus encompasses a vast genus of proteins, antibodies, nucleic acid, small molecules and other compounds having the required activity. The list of compounds recited in dependent claim 2 are not representative of this genus. First, the specification does not provide any evidence that the polypeptides PD-L1, CD24, polyglutamic and β2M have the required functional activity beyond a statement asserting such. Furthermore, the claim also includes a number of “activators” of other polypeptides, but there is no evidence that activators of these polypeptides have the required functional activity, and furthermore there is no description of particular structures that are activators of these polypeptides. Based on the disclosure, Applicants are not in possession of a genus of moieties that have the required functional activity of inhibiting uptake of the composition by a macrophage. Per MPEP 2124, "describing a composition by its function alone typically will not suffice to sufficiently describe the composition".
Therefore, only a composition for delivering a therapeutic agent to a subject in need thereof, the composition comprising a therapeutic agent and a delivery vehicle, wherein the delivery vehicle comprises a moiety comprising the CD47 self-peptide (residues 4-24 of SEQ ID NO: 1), or comprising the amino acid sequence of SEQ ID NO: 1 or comprising the amino acid sequence of SEQ ID NO: 2, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Prior Art Rejection(s)
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 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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 10 and 24-25 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Brinker et al, U.S. Patent Application 2018/0110831, published 4/26/18, filed 3/9/16 and claiming priority to 3/9/15. The earliest date to which the instant application claims priority is 4/30/21.
Claims 1 and 2 each encompass a composition for delivering a therapeutic agent to a subject in need thereof that comprises a therapeutic agent and a delivery vehicle that comprises a moiety to inhibit uptake of the composition by a macrophage, and further wherein the moiety is a CD47 polypeptide. Claim 10 further limits the “delivery vehicle” to a “lipid nanoparticle”, and the term “lipid nanoparticle” is defined in the instant specification as “a particle having at least one dimension on the order of nanometers (e.g., 1-1,000 nm) which includes one or more lipids” (¶ 124, published application).
Brinker teaches that the invention is directed “nanoparticles coated with a lipid bilayer” (¶ 3), which is encompassed by the definition of “lipid nanoparticle” taught by the instant specification, and further that these nanoparticles include “components to evade macrophage phagocytosis or enhance biodistribution and/or circulation” (¶ 3). Brinker further teaches that such a component is “at least one CD47 molecule or an active fragment thereof” and that the nanoparticle is loaded with a therapeutic cargo (see Abstract). As such, the teachings of Brinker anticipate claims 1, 2 and 10.
Claim 3 encompasses a composition of claim 2 wherein the moiety comprises a sequence selected from a group including a variant of SEQ ID NO: 2, which from residues 4-24 is identical to residues 100-120 of the full-length CD47 sequence. Thus, such variants encompass the CD47 sequence employed by Brinker. Brinker further teaches that the CD47 can be the extracellular domain fragment (¶ 6), which is also encompassed by a variant of SEQ ID NO: 1 or 2. As such, the teachings of Brinker also anticipate claim 3.
Claims 4 and 5 encompass a composition of claim 1 wherein the delivery vehicle further comprises a targeting moiety specific for binding to a target cell (claim 4) and further wherein the target cell is an endothelial cell (claim 5). Brinker further teaches that the nanoparticles of the invention may include a “targeting peptide” which binds to a “targeted cell” (¶ 160). Brinker further teaches that a target cell of the invention includes “hemangiosarcoma” (¶ 154), which is originates from endothelial cells and thus is encompassed by claim 5. As such, the teachings of Brinker anticipate claims 4 and 5.
In claim 24, the recitation directed to “for in vivo delivery of a lipid nanoparticle (LNP) to a non-hepatic cell of a subject while avoiding delivery to hepatic cells, wherein the LNP comprises a pegylated lipid conjugated to an active CD47 polypeptide, and a therapeutic agent” has been considered in the context of the entire claim, and is interpreted as an intended use for the method because it merely recites what the composition is to be used for rather than clearly indicating what the structure of the composition. See MPEP 2111.02. As such, the claim broadly encompasses any “pharmaceutical composition”. As such, the teachings of Brinker directed that meet the composition of claim 1 also meet the composition of claim 24. However, it is further noted that Brinker teaches conjugation of the CD47 molecule to a lipid via a PEG crosslinker (¶ 7). As such, the teachings of Brinker also anticipate claim 24.
Claim 25 limits the active CD47 polypeptide of claim 24 to one that comprises SEQ ID NO: 1 or 2. This further limitation is directly solely to the intended use of parent claim 24, which recites that the composition is to be used to deliver an LNP comprising CD47. As such, claim 25 is anticipated by Brinker for the same reasons as for parent claim 24.
Claims 1-4, 6, 10 and 24-25 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Kalluri et al, U.S. Patent Application 2019/0117570, published 4/25/19, filed 11/28/18 and claiming priority to 3/16/15. The earliest date to which the instant application claims priority is 4/30/21.
Claims 1 and 2 each encompass a composition for delivering a therapeutic agent to a subject in need thereof that comprises a therapeutic agent and a delivery vehicle that comprises a moiety to inhibit uptake of the composition by a macrophage, and further wherein the moiety is a CD47 polypeptide. Claim 10 further limits the “delivery vehicle” to a “lipid nanoparticle”, and the term “lipid nanoparticle” is defined in the instant specification as “a particle having at least one dimension on the order of nanometers (e.g., 1-1,000 nm) which includes one or more lipids” (¶ 124, published application).
Kalluri teaches “lipid-based nanoparticles (e.g., liposomes or exosomes) having CD47 on their surface and comprising a therapeutic agent” (see Abstract). Kalluri further teaches that “expression of CD47 on the surface of exosomes prevents phagocytosis by macrophages” (¶ 44). As such, the teachings of Kalluri anticipate claims 1, 2 and 10.
Claim 3 encompasses a composition of claim 2 wherein the moiety comprises a sequence selected from a group including a variant of SEQ ID NO: 2, which from residues 4-24 is identical to residues 100-120 of the full-length CD47 sequence. Thus, such variants encompass the full-length CD47 sequence employed by Kalluri. As such, the teachings of Kalluri also anticipate claim 3.
Claim 4 encompasses a composition of claim 1 wherein the delivery vehicle further comprises a targeting moiety specific for binding to a target cell. Kalluri further teaches that exosomes of the invention contain proteins that target them to recipient cells (e.g., at ¶ 5, 185). As such, the teachings of Kalluri also anticipate claim 4.
Claim 6 encompasses a composition of claim 1 wherein the agent comprises at least one isolated nucleoside-modified RNA molecule. Kalluri further teaches that the therapeutic agent can be an inhibitory RNA that is an siRNA (¶ 9), and that the siRNA may include “non-natural internucleoside linkages (¶ 162), which is encompassed by the “at least one isolated nucleoside-modified RNA molecule” of claim 6. As such, the teachings of Kalluri also anticipate claim 6.
Claim 10 encompasses a composition of claim 1, wherein the delivery vehicle comprises a lipid nanoparticle (LNP). The teachings of Kalluri set forth above that anticipate claim 1 are directed to a delivery vehicle that is a LNP. As such, the teachings of Kalluri also anticipate claim 10.
In claim 24, the recitation directed to “for in vivo delivery of a lipid nanoparticle (LNP) to a non-hepatic cell of a subject while avoiding delivery to hepatic cells, wherein the LNP comprises a pegylated lipid conjugated to an active CD47 polypeptide, and a therapeutic agent” has been considered in the context of the entire claim, and is interpreted as an intended use for the method because it merely recites what the composition is to be used for rather than clearly indicating what the structure of the composition. See MPEP 2111.02. As such, the claim broadly encompasses any “pharmaceutical composition”. As such, the teachings of Kalluri that meet the composition of claim 1 also meet the composition of claim 24. As such, the teachings of Kalluri also anticipate claim 24.
Claim 25 limits the active CD47 polypeptide of claim 24 to one that comprises SEQ ID NO: 1 or 2. This further limitation is directly solely to the intended use of parent claim 24, which recites that the composition is to be used to deliver an LNP comprising CD47. As such, claim 25 is anticipated by Kalluri or the same reasons as for parent claim 24.
Note
No prior art has been identified that teaches or renders obvious the specific amino acid sequences of SEQ ID NO: 1 or 2, which are shown in the specification at page 123. Each is a peptide of 24 amino acids. In SEQ ID NO: 1 (murine) and 2 (human), residues 4-24 correspond to the 21 amino acids of the “self-peptide” derived from human CD47 that was known in the prior art (e.g., Huang et al, 2021, cited above), but each sequence further includes a lysine at residue 1 with an azide (N3) modification, and a glycine at residues 2 and 3. No prior has been identified that teaches the addition of this particular combination of residues to the N-terminus of the residues corresponding to the CD47-derived self-peptide.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
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