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 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.
DETAILED ACTION
Claims 1-4 and 15-32 are pending in the instant application.
Priority
This application is a 371 of PCT/US20/56210, filed on 10/19/2020 which claims priority to the provisional application 62923498 filed on 10/19/2019.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-4) in the reply filed on 10/10/2025 is acknowledged. Claims 3-4 are withdrawn as being drawn to a non-elected group.
Newly submitted claims 17-32 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
Elected Group I (claims 1-2, 15-16,) is drawn to a conjugate of Vitamin D and a compound having G-CSF activity.
Newly submitted claims 17-24 are drawn to a conjugate of “a metabolite of Vitamin D” and a compound having G-CSF activity, wherein the particular structure of said metabolite is not disclosed.
Newly submitted claims 25-32 are drawn to a conjugate of “a carrier molecule transportable by D binding protein” and a compound having G-CSF activity, wherein the structure of said carrier molecule is not disclosed.
Claims 3-4 and 17-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/10/2025.
Claim 1-2, 15-16
Claims 1-2, and 15-16 are examined herein.
Information Disclosure Statement
The information disclosure statement (IDS) dated 10/10/2025 complies with the provisions of 27 CFR 1.97, 1.98, and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits.
Objections to the Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pg 90, para 00361). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Correction is required. See MPEP § 608.01(b).
Claim Interpretation
Claim 1 recites “is vitamin D”. This was interpreted as comprising the structures of Vitamin D1 (ergocalciferol), vitamin D2 (ergocalciferol), vitamin D3 (7-dehydrocholesterol), vitamin D4 (22-dihydroergocalciferol), or vitamin D5 (sitocalciferol). The shared structural features are shown below with the numbering scheme.
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Claims 1-4 refer to compounds having “G-CSF activity” or “GM-CSF activity.” The instant specification describes these compounds using the citation of Mehta (doi: 10.4049/jimmunol.1500861). “G-CSF” and “GM-CSF” refer to Granulocyte colony stimulating factor and Granulocyte/Monocyte colony stimulating factor, respectively. The article discusses recombinant human G-CSF (filgrastim) as being an exemplary species of this genus that is effective for treating neutropenia, which is reiterated in the instant specification (pg 83, para 00347 – pg 84, para 00349; pg 88, para 00360). The instant specification recites that both G-CSF and GM-CSF are downstream of cytokines such as IL-6 and TNFα (pg 82, para 00345). For the purposes of examination, the property of “having G-CSF activity or GM-CSF activity” was interpreted as “is G-CSF or GM-CSF” or “stimulates G-CSF or GM-CSF activity” in light of the instant specification.
Claims 15-16 refer to “a scaffold” which was defined as a
“comprising poly(ethylene glycol), polylysine, polyethyleneimine, poly(propyleneglycol), a peptide, serum albumin, thioredoxin, an immunoglobulin, an amino acid, a nucleic acid, a glycan, a modifying group that contains a reactive linker, a water-soluble polymer, a small carbon chain linker, or an additional therapeutic moiety.” (instant specification pg 5, para 0016).
The scaffold also has an open definition for its location:
“In certain embodiments, the present invention provides carriers that include those of formula
I: B-L1-S-L2-L3-C
Wherein:
B is a targeting group selected from vitamin D, a vitamin D analog, a vitamin D-related metabolite, an analog of a vitamin D related-metabolite, a peptide that binds DBP, an anti-DBP antibody, an anti-DBP antibody derivative, a nucleotide aptamer that binds DBP, or a small carbon-based molecule that binds DBP;
S is a scaffold moiety, comprising poly(ethylene glycol), polylysine…” (instant specification pg 7, para 0025-0026).
Using the definitions provided in the specification, the “scaffold” was interpreted as an intervening group between the vitamin D containing targeting group “B” and the amine-reactive group “C” which can serve as an attaching point for a protein such as G-CSF.
Objections to the Claims
Claim 1 lacks clarity because the subject is missing in the second clause. Please replace “A carrier-drug conjugate, comprising a targeting group that is vitamin D that is not hydroxylated at the Carbon 1 position stably linked to a therapeutic compound having G-CSP activity” with “A carrier-drug conjugate, comprising a targeting group that is vitamin D that is not hydroxylated at the Carbon 1 position, wherein the targeting group is stably linked to a therapeutic compound having G-CSF activity”.
Correction is required. See MPEP § 608.01(m).
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.
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.
Claims 1-2 and 15-16 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.
Claim 1,2
Claims 1 and 2 are drawn to a therapeutic compound “having G-CSF activity”. It is unclear what “activity” means in this context. There are multiple, conflicting interpretations “having G-CSF activity”: (i) the compound is G-CSF; (ii) the compound is upstream of G-CSF in a biological mechanism; (iii) the compound stimulates G-CSF; or (iv) the compound inhibits G-CSF. Because the properties implied by the claim limitation conflict such as in (iii) and (iv), one of skill in the art would not be apprised of what structure or function these compounds must have in order to satisfy the claim limitation of “having G-CSF activity”. Thus rendering this claim indefinite. Dependent claims 15-16 fail to cure these deficiencies, thus are also rendered indefinite. See “Claim Interpretation” section above.
Claim 15-16
Claims 15-16 refer to “the stable linkage comprises a scaffold” wherein it is unclear how this is to be interpreted. Firstly, applicant defines the structure of the scaffold broadly, wherein it is unclear what differentiates the “scaffold” from “the linker” given in Formula (I) (pg 8, para 0027). Secondly, because the formula is not described in the claim, the position of the scaffold relative to the vitamin D or G-CSF-activity molecule is not defined. Thus it is unclear what the function, structure, and location of this scaffold is. Because it is unclear what limitation “the scaffold” refers to, one of skill in the art would not be apprised of what structures would satisfy this claim limitation, thus rendering claims 15-16 indefinite. Examiner strongly recommends providing a formula or chemical structure in the base claim.
Claim Rejections – 35 USC § 112(a)
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 1-2 and 15-16 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.
Claim 1-2, 15-16
Claims 1-2 and 15-16 are drawn to the genus “compound having G-CSF activity”. A search of the relevant art shows that this is not a well-defined genus. Applicant can meet the written description requirement by either (i) supplying the core structure required to possess the function of “having G-CSF activity” or (ii) providing a representative number of species of compounds “having G-CSF activity”. Applicant does not provide a closed definition of this genus nor describe what core structure these compounds must possess to have the specified function. Applicant has provided a subset of “preferred” exemplary species that are variants of G-CSF (see instant spec pg 6, para 0022). However applicant has failed to provide what other species are envisaged by this genus that do not possess structural similarity to G-CSF (e.g. compounds that inhibit G-CSF activity as described in the 112(b) rejection of this claim language). As applicant has not limited the structure of “compounds having G-CSF activity” to being structurally similar to G-CSF, applicant has failed to meet the written description requirement for this genus. Please see the 112(b) rejection and “Claim Interpretation” sections above regarding other issues of interpreting this claim language.
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.
Claims 1-2 and 15-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Soliman (US9585934).
Claims 1,2, 15-16
Regarding claim 1-2 and 15-16, Soliman teaches conjugation of vitamin D to a therapeutic protein extents their half-life over non-conjugated forms (abstract). Soliman teaches that the therapeutic protein is optionally a cytokine (col 18, para 4). Soliman teaches that TNFα is one exemplary cytokine (col 74, para 2). Because applicant appears to include cytokines such as TNFα as exemplary compounds with “G-CSF activity” as discussed in the “Claim Interpretation” section above, this was found to satisfy the claim limitation of “a therapeutic compound having G-CSF activity.” Because vitamin D lacks a hydroxyl group at carbon 1, this satisfies the claim limitation “not hydroxylated at Carbon 1” (see “Claim Interpretation” section regarding the structure of Vitamin D). Soliman discloses conjugates of Vitamin D comprising a linker and a maleimide unit from which a protein can be attached (Fig 2, shown below). As seen in the structure below, the linker is conjugated through the hydroxyl of carbon 3 of vitamin D.
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This structure is identical to the one in the specification, reproduced below (instant spec pg 60, para 00255). Thus must necessarily comprise “a scaffold” sufficient to satisfy the claim limitation of “the stable linkage comprises a scaffold.” Please see the 112(b) rejection and the “Claim Interpretation” section regarding this particular claim language.
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Soliman teaches the maleimide unit can be used to couple to cysteine groups on a protein (pg 8, para 8).
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.
Claims 1-2 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Carter (US20110171168) in view of Soliman (US9585934).
Claim 1, 2
Carter teaches a composition comprising an hG-CSF analogue which is defined as a polypeptide having an amino acid sequence that differs from wild-type hG-CSF (SEQ ID NO: 1) at one or more locations that exhibits G-CSF activity (pg 2 para 0038), such as mutations at the locations indicated below (pg 3, para 0057).
hG-CSF TPLGPASSLPQSFLLKCLEQVRKIQGDGAALQEKLCATYKLCHPEELVLLGHSLGIPWAP 60
Carter_X XPLGPASSLPQSFLXKCLXQVRKIxGDGAAXQEXLCATYXLCHPEEXXXLGHSXGIPWAP 60
************* *** ***** ***** ** ***** ****** **** ******
hG-CSF LSSCPSQALQLAGCLSQLHSGLFLYQGLLQALEGISPELGPTLDTLQLDVADFATTIWQQ 120
Carter_X LSSCPSQALQLAGCLSQLHSGLFLYQGLLQALEGISPELGPTLDTLQLDVAXFATTIWQQ 120
*************************************************** ********
hG-CSF MEELGMAPALQPTQGAMPAFASAFQRRAGGVLVASHLQSFLEVSYRVLRHLAQP 174
Carter_X MEEXGMAPALQPTQGAMPAFAXAXQXRAGGVLVASHLQSFLEVSYRVLRHLAQP 174
*** ***************** * * ****************************
Carter teaches fusion proteins of hG-CSF with a heterologous signal sequence (pg 5, para 0070) or other non-polypeptide moieties (pg 5, para 0074). Carter teaches administering the hG-CSF analogue with at least one other active compound (pg 11, para 0138), wherein the other active compound is optionally vitamin D (pg 11, para 0139). Because vitamin D lacks a hydroxyl group at carbon 1, this satisfies the claim limitation “not hydroxylated at Carbon 1” (see “Claim Interpretation” section regarding the structure of Vitamin D).
Carter does not teach conjugating the vitamin D to the hG-CSF analogue, nor do they specify that this conjugation occurs at carbon 3 of vitamin D.
Soliman discloses conjugates of Vitamin D comprising a linker and a maleimide unit from which a protein can be attached (Fig 2, shown below). As seen in the structure below, the linker is conjugated through the hydroxyl of carbon 3 of vitamin D.
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This structure is identical to the one in the specification, reproduced below (instant spec pg 60, para 00255).
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Soliman teaches the maleimide unit can be used to couple to cysteine groups on a protein (pg 8, para 8). Soliman teaches conjugation of vitamin D to therapeutic protein extents their half-life over non-conjugated forms (abstract).
It would have been obvious to combine the teachings of Carter and Soliman because (1) Carter teaches vitamin D can be co-administered with G-CSF analogues and that G-CSF is amenable to conjugation with a linker; and (2) Soliman discloses a linker that can be attached to vitamin D that is amenable to attachment to a protein. One of skill in the art would have had a reasonable expectation of success because Carter teaches G-CSF can be conjugated while retaining its biological functions and Soliman teaches that vitamin D can be conjugated to a protein in order to enhance the half-life of the agent that is coupled to it. Given that Carter also teaches it is advantageous to combine G-CSF and vitamin D in a combination therapy regime, one of skill in the art would have found it obvious to conjugate these two components together.
Claim 15, 16
Carter teaches the hG-CSF analogue may incorporate a linker sequence such as a peptide sequence that intervenes between the hG-CSF analogue and a heterologous moiety (pg 5, para 0068). Because the “scaffold” as defined in the claim and the specification is indistinguishable from this exemplary linker, the linker sequence of Carter satisfies the limitation of “the stable linkage comprises a scaffold.”
Relevant Prior Art
Kawase (doi: 10.1055/s-2004-825728) describes the benefits of combination therapies comprising an analogue of vitamin D3 (1,25-(OH)2-vitamin D3) and hG-CSF in order to induce proliferation of bone marrow progenitor cells (abstract).
“Based on this proposal, we raised a working hypothesis that 1,25(OH)2D3 augments hG-CSF-induced granulocytic differentiation in the present study. To our surprise, however, the combinational treatment appeared to promote monocytic but not granulocytic differentiation, indicating that the differentiative action of 1,25(OH)2D3 is augmented by hG-CSF. G-CSF has generally been held to act specifically on cells committed to the granulocytic lineage in promoting granulocytic differentiation by upregulating its specific receptor” (pg 450, col 2, para 3).
In essence, the teachings of Kawase offer nuance in the selection of the particular vitamin D analogue when combined with hG-CSF, and that stimulation of G-CSF versus GM-CSF activity is dependent on the structure of the vitamin D compound employed in the combination therapy.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA ANN ESSEX whose telephone number is 571-272-1103. The examiner can normally be reached Mon - Fri 8:30-5:00.
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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