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 .
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.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2021/064156, filed 12/17/2021, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 63/127,877, filed 12/18/2020.
Information Disclosure Statement
The information disclosure statement, filed 01/31/2024, is considered, initialed and is attached hereto.
Status of the Claims
Claims 1-15, 18, 21, 56 and 62-63 are pending; claims 3, 4, 6-8, 10-13, 15, 18, 21, 56 and 62-63 are amended; no claims are withdrawn, and claims 16, 17, 19, 20, 22-55 and 57-60 are canceled. Claims 1-15, 18, 21, 56 and 62-63 are examined below.
Claim Interpretation
The following claim language is interpreted on the record for clarity of the record.
The claim language “retinol binding protein (RBP)” is interpreted as defined by the originally filed specification at para [0039]. Para [0039], indicates that "Retinol binding protein" or "RBP," as used herein, refers to a family of polypeptides capable of binding retinol. RBP is hepatically synthesized and responsible for transporting vitamin A from the liver to other tissues. RBP is capable of binding vitamin A, retinoids, derivatives, and conjugates thereof. Any RBP known in the art, or a retinol-binding portion thereof can be used in the methods disclosed herein. In some aspects, the RBP is a human RBP, or a retinol-binding portion thereof. In humans, there are at least 6 RBPs, including RBP1 (UniProtKB - P09455), RBP2 (UniProtKB - P50120), RBP3 (UniProtKB - P10745), RBP4 (UniProtKB - P02753), RBP5 (UniProtKB - P82980), and RBP7 (UniProtKB - Q96R05). In certain aspects, the RBP is derived from a human RBP. In some aspects, the RBP is a non-human primate RBP. In some aspects, the RBP is a mouse or rat RBP, or a retinol-binding portion thereof. In some aspects, the RBP is derived from a mouse or rat RBP.
Based on Applicant’s specification, the indicated claim language is considered limited to retinol binding protein that is the family of proteins hepatically synthesized and responsible for vitamin A transport as indicated. This language does not encompass other binding proteins that bind retinol (those outside the described family of polypeptides referred to as “retinol binding proteins), for example, does not encompass binding proteins such as antibodies that bind retinol.
Claim Rejections - 35 USC § 112
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.
Written Description
Claims 1-15, 18, 21, 56 and 62-63 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The recited claims recite the language “a modified retinol binding protein (RBP)” (claim 1). Claim 4 further recites “the modified RBP comprises a heterologous moiety”. The claims refer to a family of polypeptide known as “retinol binding proteins”, these proteins hepatically synthesized and responsible for transporting vitamin A from the liver to other tissues. RBP is capable of binding vitamin A (see referring to the claim interpretation, as referenced from the originally filed specification above). However, as noted above (under claim interpretation), the language “modified retinol binding protein” refers to proteins capable of a particular function, namely binding retinol, and as indicated by the specification.
Regarding the originally filed specification, the specification indicates “modified” as meaning that the RBP can be modified to enhance binding affinity of the RBP for retinoid or fat-soluble protein (see para [0076]). However, the specification does not indicate any particular modification or describe what structural changes/features would be necessary in order to achieve such enhancement. Put another way, the specification fails to describe any particular examples of modification in terms of structure or structural feature which distinguishes RBPs from modified RBPs, as presently claimed.
As discussed in further detail below (see under 35 U.S.C. 112(b)), claim 4 does recite “the modified RBP comprises a heterologous moiety” and further at claim 5, “wherein the heterologous moiety comprises biotin” (see also claim 6), however it is unclear from recited claim language and language at the specification if biotin, for example is the modification (is what makes the RBP modified) or rather if modified RBP also includes heterologous moiety that is biotin.
As a result, the language as recited as the claims encompasses a large and variable genus of products that may be characterized by substantial variability. For example, “modified” could encompass limitless possible modifications as there is no particular limitation on the claimed language (for example could be sequence modification to the RBP itself, or further could encompass additional heterologous components provided linked/attached to the RBP). Even in the case of modified RBPs which are limited to only sequences changes to the RBP itself (i.e., variants that include any possible combination of substitutions, deletions or additions), the claims would still encompass a large and variable genus, as there is no minimum or maximum number of possible sequence changes/alterations. The claims encompass any possible RBP variant sequences, limited in terms of desired binding, as discussed in detail above.
The claim scope is potentially enormous depending on how many of the products that meet the structural requirements (modified protein with claimed exterior) would also meet the functional requirements (binds exterior surface exposed retinoid or a fat soluble vitamin, as recited at claim 1, particularly vitamin A or DiVa-PEG-DiVa, as at claim 3).
Referring to the actual reduction to practice as disclosed in the originally filed specification Examples do not appear to use modified RBP, see as described at Example 1 (para [0095]), Applicant discloses the use of native human retinol binding protein RBP4, which does not appear to be a modified form of RBP. The specification lacks any specific or limiting examples as to what would be considered “a modified RBP” as encompassed by the recited claims.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members.
It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date” (AbbVie, 759 F.3d at 1298, reiterating Enzo Biochem, Inc., 323 F.3d at 964)(emphasis added).
In the present case, however, there is insufficient evidence of such an established structure-function correlation in the case of “modified retinol binding proteins” that bind retinoid or fat-soluble vitamins as presently claimed.
Regarding the prior art, and protein modifications to structure in relation to binding function, the prior art recognized that even small changes to a proteins structure, see for example, the teachings of Harlow et al. (Antibodies, A Laboratory Manual, Cold Spring Harbor laboratory, 1988, pages 25-26 and 37-59) which describe how the steps of the humoral immune response to an immunogen are dependent on APC, T-cell and B-cell recognition and processing of the immunogen in ways well known in the art to be highly unpredictable and heavily influenced by the particular immunogen and the specifics of the immunization protocol. Harlow et al. teach that even small changes in structure, such as loss of a single hydrogen bond, can profoundly affect antibody-antigen interaction (p. 25, last paragraph to page 26, second paragraph).
See also Jeffrey et al., Protein species and moonlighting proteins: Very small changes in a protein’s covalent structure can change its biochemical function, Journal of Proteomics, 134, (2016), p. 19-24, which refers to examples wherein post-translational modifications to proteins, namely changes to even a single amino acid residue (a single mutation) can impact function, see teaching a single mutation can cause new or a switch between functions (abstract, even a small difference in sequences or post-translational modification can result in a large difference in function, see also conclusion pages 22-23). Jeffrey teach with such small differences in protein covalent structure resulting in differences in protein function, the prediction of protein function by searching for amino acid sequence homologs, although a very powerful and often successful method, can sometimes result in an incorrect prediction, and testing the predictions in vitro or in vivo is still preferable, although far more difficult to do.
Jeffrey supports that short of testing modified structures, one cannot readily visualize what species would or would not retain the desired binding (to retinoid or fat soluble vitamin) as claimed, other than the specific examples of RBP as referenced in the specification binding to retinol/vitamin A.
The specification provides no indication as to what is encompassed by the language “modified” in terms of “modified retinol binding protein” as claimed. In contrast to the extremely large and variable genus, the originally filed specification provides no specific examples of what would be considered a modified RBP such that one could correlate a given structure with function as claimed. Further, given the unpredictability regarding what modification could or would be tolerated and still retain binding function as claimed, there is insufficient evidence to support Applicant is in possession of the claimed genus, modified RBP.
Further, claim 56 recites “the liposome is capable of preventing or treating a disease or condition in a subject”, the liposome referring to “liposome” having an “exterior surface of the liposome comprises a retinoid or a fat-soluble vitamin”. The claims broadly encompass a genus of liposome described by limited structural feature(s) (exterior surface of the liposome comprises a retinoid or fat soluble vitamin) and by functional ability, namely is “capable of preventing or treating a disease or condition in a subject”. Based on Applicant’s originally filed specification, it does not appear that the liposome itself as presently claimed is capable of preventing or treating disease, but rather could potentially be useful as a vehicle for delivery of a component intended as a treatment (see e.g., paras [0004] and [0072]). The specification does not support, for example, retinoid or fat soluble vitamin, such as Vitamin A or DiVa-PEG-DiVa as therapeutic.
The claims are extremely broad, for example the liposome itself is not described as carrying any particular therapeutic and further the claims are not limited with respect to any disease/condition that is to be treated or prevented. Even further, regarding the breadth of the claims, as presented the claims encompass preventing any disease or condition in any subject at any time (including any time in the future), as there are no limitations on subject to be treated.
It is not predictable that a liposome, as recited at claim 1, is capable of treating or preventing any and all diseases/conditions at any time in any subject. See for example, Hallenbeck, Ken. “A downside to liposome drug delivery”, ASMB Today. (2023). https://www.asbmb.org/asbmb-today/science/030723/a-downside-to-liposome-drug-delivery. Accessed: 06/10/2026, Hallenbeck suggest liposome administration of treatments may have negative effects for those who are immunocompromised or who have bone marrow infections, since some experiments suggest macrophages in the bone marrow underwent pro-inflammatory activation and showed signs of stress, such as lipid accumulation in the endoplasmic reticulum, leading to a decreased ability to create red blood cells and important immune cell types like monocytes.
Further, although there are no working examples, it is acknowledged that the originally filed specification suggests liposomes for prevention or treatment of a series of disease (see listed at para [0020]), however it would be expected that such liposomes capable of treatment or disease prevention would include a particular therapeutic agent (e.g., a therapeutic RNA, as referred to at para [0004]), and the claims are not limited to any particular therapeutic. It is not expected that a liposome as presently claimed would be effective for prevention or treatment.
For all these reasons, there is insufficient written description to support Applicant was in possession of the broadly recited genus of liposome (described by limited structural feature(s) (exterior surface of the liposome comprises a retinoid or fat soluble vitamin) and by functional ability, namely is “capable of preventing or treating a disease or condition in a subject”).
New Matter
Claim 11 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 11 recites “the liposome is:…a biologically active molecule” or “both (i) and (ii)”. Referring to the originally filed specification, the specification does support liposomes comprising a biologically active molecule (see for example, para [0013]), however there is no support for a liposome that is a biologically active molecule.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1-15, 18, 21, 56 and 62-63 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1 (the language “modified RBP”), and claim 4, 5 and 7, claim 4 recites “wherein the modified RBP comprises a heterologous moiety”, and claim 5, “wherein the heterologous moiety comprises biotin” (see also claim 7, “the modified RBP comprises a biotin”. It is not readily clear what is or is not encompassed by the language “modified RBP”, for example, it is not clear if the claim refers to a modified RBP which is modified by an additional binding moiety, just as that heterologous binding moiety as recited at claims 4, 5 and 7, or rather if “modified” refers to some other modification to the sequences/structure of RBP(s) that is distinct from an additional component that is something like a heterologous binding moiety. As such, for example, it is unclear if at claims 4, 5 and 7, if the heterologous moiety (biotin) is the modification that makes the RBP a “modified RBP” or if this moiety is in addition to/an additional part included with the modified RBP. As such, the boundaries of what is encompassed by the claim are not readily clear and as such, the claim is indefinite.
Claim 3 recites “wherein the retinoid or the fat-soluble vitamin comprises vitamin A or a DiVa-PEG-DiVa (DPD) construct”, the language suggests that either of the retinoid or the fat-soluble vitamin can be either of Vitamin A or a DiVa-PEG-DiVa, however this language is confusing and misleading because only vitamin A is considered to be a fat soluble vitamin, and it appears only DPD constructs would or could be considered as retinoids. As a result, the recited language is indefinite.
Claim 11 recites “the liposome is…”a biologically active molecule” or is “both (i) and (ii)”, which both means the liposome is both a lipid nanoparticle and a biologically active molecule. The recited language is indefinite because a liposome and a biologically active molecule are generally not considered to be one and the same, for example, a liposome is not a singular molecule, rather it is generally in the art considered to be a spherical vesicle made up of many molecules (e.g., phospholipids). As a result, the claim language is indefinite because it is not readily clear what is encompassed by the recited language given that the subspecies are not all subspecies considered to be liposomes.
Claim 56 recites, “further comprising administering the liposome”, the language “further comprising reads as though the step at claim 56 follows the steps performed at claim 1 (contacting with the immobilized surface). The recited language is confusing because it would be considered feasible to administer the liposome in reference to the liposome binding the modified RBP at the surface of claim 1. It appears that the claimed limitation requires some preferred order of events, or additional clarification such that one can readily visualize the claims and the order of the actions taken as part of the recited method.
Claims 62 and 63 are each claims directed to product inventions (namely a kit), the claims comprising only an intended use, and reciting no particular or required structure or reagents. For example, the claims recite the kits are for the intended uses of “measuring the relative RBP-binding affinity of a liposome in a sample according to the method of claim 1” (claim 62) or for “assaying the relative RBP-targeting bioperformance of a liposome in a sample according to the method of claim 1”, however there is no indication what structures/reagents are required for achieving these clinical goals. For example, a kit comprising nearly any usable component/reagent necessary for such an assay as recited could read on the claims (for example, merely comprising a buffer usable for detection as claimed).
Additionally, claim 63 recites the limitation "the relative RBP-targeting bioperformance of a liposome" lines 1-2. There is insufficient antecedent basis for this limitation in the claim, and additionally it is not readily clear what is encompassed assaying for “relative RBP-targeting bioperformance”, particularly in a manner that would allow one to visualize what kit components would be necessary/encompassed by the recited language in addition to merely just detecting a liposome (in terms of detecting presence, as suggested by the preamble of claim 1).
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.
Claim(s) 62 and 63 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by FI95806B.
FI 95806 recites RBP immobilized on an affinity gel (i.e., RBP associated with an immobilized surface), the only structural component/product recited at the method of independent claim 1, the claim referenced by the present kit claims. Based on example referenced in the originally filed specification RBP (including native) is encompassed by the “modified” (for example, given broadest reasonable interpretation, “modified” could merely mean modified by being immobilized).
FI 95806 fails to use the terminology “kit”, however, in the present case the terminology “kit” is not considered to further limit the scope of the claim beyond requiring some reagent/component usable in performing the intended use, as it does not clearly invoke additional ingredients, reagents, etc., or provide antecedent basis for terms appearing in the body of the claim (such as a specific packaging or container elements, for example). See MPEP 2111.02. See as discussed in more detail previously above under 35 U.S.C. 112(b), the kit claims fail to indicate any particular components provided as part of a kit as claimed.
Regarding the language at the preamble of the claims, namely “for measuring the relative RBP-binding affinity of a liposome in a sample” and “for assaying the relative RBP-targeting bioperformance of a liposome in a sample”, if a prior art structure is capable of performing the intended use as recited in the preamble, then it meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997) and MPEP 2111.02. Applicant is also reminded that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04. In this case, no clear structural differences are invoked by the recitation of an intended use.
Conclusion
Independent claim 1, a method of detecting a liposome in a sample comprising contacting with a modified retinol binding protein (RBP) associated with an immobilized surface; wherein an exterior surface of the liposome comprises a retinoid or a fat-soluble vitamin, appears to be free of the prior art. However, see pending grounds of rejection as detail above.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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