DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s Response to Election/Restriction Filed, Amendment, and Arguments/Remarks, filed 23 January 2026, have been entered. Claims 1-9, 12-13, 17-18, 22-24, 26-27, 29, and 32 are currently pending. Claims 1, 24, 26, 27, and 29 are independent claims. Applicant’s election with traverse of the invention of Group I, drawn to a vector for liver and/or splenic phagocyte-specific expression and a cell comprising the vector, is acknowledged.
Regarding the Restriction Requirement, Applicant argues that:
the Merlin reference cited by the Office destroys unity; and
the vaccine (Group II, claim 26) does not lack unity with the claim directed to the vector insofar as the vaccine of claim 26 comprises the vector of claim 1.
However, this is not agreed.
Regarding argument A), as described in the prior action, Merlin was cited for teaching a vector for liver macrophage-specific (e.g., liver sinusoidal endothelial cells, dendritic cells, or hepatic macrophages) expression, wherein the vector comprises a transgene (e.g., miRNAs) operably linked to one or more expression control sequences (e.g., ICAM, Flk1, Tie2, VEC, or CD11b) [column 4 ¶ 2-3, column 9 ¶ 1-3, Figure 1]. Because claim 1 is anticipated by Merlin & Follezi 2019, the remaining claims lack the same or corresponding special technical feature and as such, lack unity. The expression “special technical features” means those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art. The requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. Therefore, a unity of invention does not exist among Groups I-IV.
Regarding argument B), the shared technical feature between the invention of Group I and Group II is the vector of claim 1. As described above, Merlin teaches all of the limitations of the vector of claim 1. As such, the shared technical feature is not a special technical feature and a unity of invention does not exist between Groups I and II.
Therefore, Applicant’s arguments do not overcome a finding of a lack of unity of invention, and the restriction requirement is made FINAL.
Additionally, Applicant’s election of the following species:
Phagocytes: a. Macrophage: ii. MRC1+ macrophage;
Phagocyte-specific promoters and/or enhancers: a. MRC1 promoter and/or enhancer
in a reply filed 23 January 2026 is acknowledged.
While Applicant has not indicated whether these elections of species have been made with or without traverse, Applicant has not provided any arguments traversing the election of species requirement(s). Therefore, the election of species is considered to have been made without traverse.
Claims 26, 27, and 29 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.
Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-4, 6-9, 12-13, 17-18, 22-24, and 32 are currently pending in the application and under examination to which the following grounds of rejection are applicable. An action on the merits follows.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2021/084276, filed 03 December 2021, which claims priority to United Kingdom Application 2019108.6, filed 03 December 2020. Filing of a certified copy of the United Kingdom Application 2019108.6, filed 03 December 2020 is acknowledged.
Thus, the earliest possible priority for the instant application is 03 December 2020.
Information Disclosure Statement
The information disclosure statements filed 13 July 2023 and 23 February 2026 have been considered by the Examiner. Examiner notes the filing of IDS Size Fee assertions for the IDS filed 23 February 2026, as required under 37 CFR 1.98, indicating that no IDS size fee is required under 37 CFR 1.17(v) at this time.
37 CFR 1.821-1.825
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2), see for example specification page 81 lines 23-29 wherein the 2) linker sequence, 4) linker sequence, and 6) termination sequence; specification page 84 lines 22-23; and specification pages 84 line 24, page 85 lines 27 and 31, page 86 lines 3, 13, and 28, and page 87 line 21. However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below and on the Notice to Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures which is attached to this communication.
Specifically, specification page 81 lines 23-29 and specification page 84 lines 22-23 disclose amino acid and/or nucleotide sequences but do not include any sequence identifiers. Additionally, specification pages 84 line 24, page 85 lines 27 and 31, page 86 lines 3, 13, and 28, and page 87 line 21 recite “Seq 1”, “Seq 2”, “Seq 3”, “Seq 4”, “Seq 5”, “Seq 6”, and “Seq 7”, respectively, accompanying a specifically defined sequence without the “ID NO:” to indicate a reference to the sequence listing. If the unidentified sequences of specification page 81 lines 23-29 wherein the 2) linker sequence, 4) linker sequence, and 6) termination sequence; specification page 84 lines 22-23; and specification pages 84 line 24, page 85 lines 27 and 31, page 86 lines 3, 13, and 28, and page 87 line 21 are included in the submitted sequence listing, Applicant must amend the claims and specification and/or drawings to comply with the sequence identification requirements. Alternatively, if the unidentified sequences of specification page 81 lines 23-29 wherein the 2) linker sequence, 4) linker sequence, and 6) termination sequence; specification page 84 lines 22-23; and specification pages 84 line 24, page 85 lines 27 and 31, page 86 lines 3, 13, and 28, and page 87 line 21 are not included in the presently submitted sequence listing, Applicant must submit an updated sequence listing in compliance with 37 CFR 1.821(c)-(d) and 37 CFR 1.825(b). See also the attached Notice to Comply.
APPLICANT IS GIVEN A THREE MONTH EXTENDABLE PERIOD WITHIN WHICH TO COMPLY WITH THE SEQUENCE RULES, 37 CFR 1.821-1.825. Failure to comply with these requirements will result in ABANDONMENT of this application under 37 CFR 1.821 (g). Extension of time may be obtained by filing a petition accompanied by the extension fee under the provisions of 37 CFR 1.136. In no case may an applicant extend the period for response beyond the six month statutory period. Applicant is requested to return a copy of the attached Notice to Comply with the response.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, including into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The use of the terms “Pfu ultra II” on page 84 line 15, “SensoQuest GmbH” on page 84 line 16, “High Pure PCR product purification kit” on page 84 line 17, “Jetquick” on page 84 line 18, “Cell Factory” on page 89 line 21, “IMDM” on page 90 line 22 and page 92 lines 6 and 8, “7-Tesla MR scanner” on page 91 line 31, “MACS” on page 92 line 11, “FACSCanto II” on page 92 line 26, “Symphony” on page 92 line 26, “7-AAD Viability Staining Solution” on page 92 lines 28-29, “Killik OCT embedding medium” on page 93 lines 6-7, “TCS SP8 Laser Scanning Confocal” on page 93 line 17, “HC PL FLUORAR 10X (NA 0.3) Dry” on page 93 line 17, “HC PL APO CS20X (NA 0.7)” on page 93 lines 17-18, “Nanodrop 8000” on page 94 line 2 and 8, and “TaqMan” on page 94 lines 12, 13, and 14, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 1-4, 6-9, 12-13, 17-18, 22-24, and 32 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.
Claims 1, 2, 3, 6, 7, 8, 9, 23 recite a plurality of “and/or” conjunctions. While this may be a convenient means for Applicant, such legalese renders the claims indefinite. For example, in claim 2 the control sequence cannot be simultaneously be each of the structurally different sequences of (a) and (b). To put it another way, the control sequence cannot be both a miRNA target sequence and a phagocyte-specific promoter. Appropriate correction is required.
Claim 6 and 7 each recite “a fragment thereof”, which is indefinite because it is unclear which fragments of the recited promoters and/or enhancers would satisfy the claim as being a “phagocyte-specific promoter and/or enhancer”. For example, it is unclear how much of and what regions of the promoters and/or enhancers would need to be retained. As such, the metes and bounds of the claims cannot be determined.
Claims 22 and 23 each recite “substantially” in line 1 of each claim. The term “substantially” in claims 22 and 23 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear how much expression would be considered to be “substantially not expressed” according to claim 22 nor how much expression would be considered to be “substantially only expressed” according to claim 23. The specification provides examples of relative expression levels for “substantially not expressed” and “substantially only expressed”, but does not provide a limiting definition of the word “substantially” nor the phrases “substantially not expressed” nor “substantially only expressed” [page 19 lines 11- page 20 line 8]. The specification provides a definition for “substantially devoid”, which itself incorporates relative language and so cannot be relied on to provide a clarifying limiting definition of “substantially” [page 25 lines 25-31]. As such, the metes and bounds of the claims cannot be determined.
Further, claim 22 recites “when transduced by the vector” in line 2, which is indefinite because claim 1 does not require that the vector be a viral vector, and so it is unclear whether “transduced by” is meant to be further limiting to require that the vector be a viral vector or whether “transduced by” is meant to generally recite any introduction of the vector into the cell. As such, the metes and bounds of the claim cannot be determined.
Claims 4, 12-13, 17-18, 24 and 32 are indefinite insofar as they depend from claim 1.
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, 2, 6, and 7 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 6 and 7 each depend on claim 2, which depends on independent claim 1, and each recite “a fragment thereof” in lines 9-10 and 2-3, respectively.
The specification recites, “A fragment of any of these promoters (or variants thereof) may be used, provided that the fragment retains the capacity to drive phagocyte-specific expression of a transgene which is operably coupled to the promoter. A skilled person will be able to arrive at such fragments using methods known in the art. The fragment may be, for example, at least 200 nucleotides, at least 300 nucleotides, at least 400 nucleotides, at least 500 nucleotides, or at least 1000 nucleotides in length.” [page 35 lines 1-6] The specification also recites, “A fragment of any of these enhancers (or variants thereof) may be used, provided that the fragment retains the capacity to drive phagocyte-specific expression of a transgene which is operably coupled to the enhancer. A skilled person will be able to arrive at such fragments using methods known in the art. The fragment may be at least 200 nucleotides, at least 300 nucleotides, at least 400 nucleotides, at least 500 nucleotides, or at least 1000 nucleotides in length.” [page 39 lines 6-11].
The specification also teaches, “In one aspect, the present invention provides a vector comprising an MRC1 promoter. Suitably, the transgene is operably linked to an MRC1 promoter. Any suitable method may be used to identify an MRC1 promoter, for example by using promoter prediction tools or by using a sequence immediately upstream to the MRC1 open reading frame. Suitably, an MRC1 promoter may be about a 0.2-5 kb, 0.5-5 kb, 1-2 kb, or about 1.8 kb sequence immediately upstream to the MRC1 open reading frame. In some embodiments, the MRC1 promoter comprises or consists of a nucleotide sequence which is at least 70% identical to SEQ ID NO: 1 or a fragment thereof. Suitably, the MRC1 promoter comprises or consists of a nucleotide sequence which is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 1 or a fragment thereof. In some embodiments of the invention, the MRC1 promoter comprises or consists of the nucleotide sequence SEQ ID NO: 1 or a fragment thereof.“ [page 35 lines 15-27].
The specification does not recite any limiting definition for “a fragment thereof”; nor does the specification recite any particular functions other than the ability to drive phagocyte-specific expression (e.g., binding interactions), sequences, nor domains which would be necessary to be retained within the fragment of the promoter and/or enhancer to maintain the ability to drive phagocyte-specific expression. The specification does not teach any structural limitations for fragments which retain the recited function(s). The specification does not provide guidance as to the nucleotides which could be modified such that the sequence would retain the necessary function(s). The specification teaches ranges for upstream sequences which be options for an MRC1 promoter, but does teach a minimum size or minimal region(s) necessary to retain the recited function(s).
The examples in the specification teach the use of a single MRC1 promoter sequence. Example 1 describes a platform to express therapeutic gene products from an MRC1-expressing phagocytic cell in the liver and spleen, wherein a lentiviral vector (LV) was designed to comprise the MRC1 promoter (i.e., SEQ ID NO: 1) driving a transgene, and wherein the MRC1 is a 1.8 kb sequence immediately upstream to the mouse Mrc1 open reading frame [page 79 lines 8-14]. Example 1 also teaches adding enhancer sequences normally found in the Mrc1 locus to the LV design, such that mouse enhancer 6 (i.e., SEQ ID NO: 27) was inserted upstream of the Mrc1 promoter [page 79 lines 27-30].
The examples do not teach the use of any other promoter nor any other enhancer. The examples do not teach the use of any fragments of the Mrc1 promoter nor any fragments of the Mrc1 enhancer.
Therefore, a written description for a fragment of a promoter and/or enhancer is lacking within the application as filed. As such, claims 1, 2, and 6-7 fail to comply with the written description requirement and do not reasonably convey to one of skill 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 Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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) 1-4, 6-9, 24, and 32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kambara et al. [2015, The American Journal of Pathology, 185(1), 162-171, IDS], as evidenced by Moseman et al. [2013, The Journal of Immunology, 191(11), 5615-5624].
Regarding claim 1, Kambara discloses a bacterial artificial chromosome (BAC) vector comprising a diphtheria toxin receptor (DTR) transgene operably linked to an MRC1 promoter, wherein the BAC comprises 133 kbp upstream of the MRC1 start codon which lies within MRC1 exon 1 [column 3 ¶ 4- column 4 ¶ 2, Figure 1A]. Kambara also discloses that the MRC1 promoter drives transgene expression in MCR1+ M2 macrophages within the liver and spleen [column 3 ¶ 3, column 8 ¶ 3, Figure 1C].
Kambara does not explicitly teach that the mouse MRC1 promoter is comprised within the 133 kbp upstream of the MRC1 start codon.
However, Moseman teaches that the mouse Mrc1 promoter region is included within 800 bp upstream of the transcription start site, and that the transcription start site is 50 bp upstream of the translation start codon [column 4 ¶ 8, column 12 ¶ 4, Figure 4E].
Regarding claims 2 and 6-7, Kambara discloses wherein the BAC vector comprises a phagocyte-specific MRC1/CD206 promoter [column 3 ¶ 4- column 4 ¶ 2, Figure 1A].
Regarding claims 3-4 and 32, Kambara discloses wherein the phagocyte is a liver or a splenic MCR1+ M2 macrophages [column 3 ¶ 3-column 4 ¶ 3, column 8 ¶ 3, Figure 1C].
Regarding claims 8-9, note that claims 8-9 as written further limit an option of claim 2 without requiring the inclusion of that option. Therefore, claims 8 and 9 are required limitations of the invention only when the option of claim 2(b) one or more miRNA target sequences is the selected option. Accordingly, claims 8-9 encompass wherein an alternative option of claim 2 is present in the invention without the further limitations introduced by claims 8 and 9. As such, by disclosing an invention wherein the vector comprises 2(a) a phagocyte-specific promoter, Kambara anticipates claims 8 and 9 in that claims 8-9 add no further limitations to the invention.
Regarding claim 24, Kambara discloses a cell comprising the BAC vector (i.e., fertilized one-cell embryos from C57BL/6 mice) [column 4 ¶ 2].
Accordingly, by teaching all of the limitations of claims 1-4, 6-9, 24, and 32, Kambara anticipates the instant invention as claimed.
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.
Claim(s) 1-4, 6-9, 12-13, 17-18, 22-24, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over He & Marneros [2014, Journal of Biological Chemistry, 289(12), 8019-8028]; in view of Kambara et al. [2015, The American Journal of Pathology, 185(1), 162-171, IDS]; Zhang et al. [2016, Biomaterials, 84, 1-12]; Zhu et al. [2015, Oncology Reports, 34, 2643-2655]; Geisler & Fechner [2016, World Journal of Experimental Medicine, 6(2), 37-54]; and De Palma et al. [2008, Cancer Cell, 14,299-311, IDS].
Regarding claim 1, He teaches a vector for MCR1+ macrophage specific expression, wherein the vector comprises a transgene (i.e., luciferase) operably linked to an expression control sequence, wherein the expression control sequence is the human MRC1 promoter [column 4 ¶ 2-3, column 6 ¶ 5, Supplemental Figure S1A].
He does not teach the intended use wherein the vector is for liver or splenic-specific expression.
However, Kambara teaches that the MRC1 promoter drives transgene expression in MCR1+ M2 macrophages within the liver and spleen [column 3 ¶ 3, column 8 ¶ 3, Figure 1C]. Kambara also teaches that M2 macrophages upregulate MRC1 and are able to promote tissue remodeling, angiogenesis, and tumor development [column 2 ¶ 1].
Additionally, Zhang teaches that during cancer development and treatment, such as in hepatocellular carcinoma (HCC), tumors are infiltrated by tumor-associated macrophages (TAMs), which are recruited in the monocyte precursor form from the peripheral blood and stimulate tumor progression by facilitating angiogenesis, invasion, and metastasis, and suppressing antitumor immunity [column 2 ¶ 2]. Zhang further teaches that TAMs are typically non-inflammatory M2-type macrophages which specifically express CD206/MRC1 [column 3 ¶ 2]. Zhang also teaches targeting CD206/MCR1-expressing TAMs to treat tumors resistant to conventional therapy, wherein targeting the TAMs inhibited tumor growth and lung metastasis [abstract, column 3 ¶ 4].
Further, Zhu teaches specifically targeting macrophages in the liver, such that CD206/MRC1 is highly expressed in human hepatocellular carcinoma (HCC) tissues compared to the level in peri-carcinoma tissue, and that the macrophage blocker GdCl3 suppresses HCC progression by downregulating the expression of CD206 in M2 TAMs, thereby reducing the invasiveness of HCC cells [abstract, column 2 ¶ 2, column 14 ¶ 1, column 15 ¶ 1, column 19 ¶ 2]. Zhu also teaches that the reduction of invasiveness is possibly by affecting the secretion of cytokines from the M2 macrophages [column 19 ¶ 2].
Therefore, given the teachings of Kambara that the M2 macrophage-specific MRC1 promoter drives transgene expression in liver and spleen, the teachings of Zhang that targeting CD206/MCR1+ macrophages inhibits tumor growth and metastasis, and the teachings of Zhu that targeting CD206/MCR1+ macrophages in HCC reduces the invasiveness of HCC cells by affecting the secretion of cytokines from the macrophages, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to target TAMs in an HCC tumor to modulate TAM secretion and reduce tumor growth, invasiveness, and metastasis.
Regarding claim 2 and 6-7, He teaches wherein the vector comprises a macrophage-specific MRC1 promoter [column 4 ¶ 2-3, column 6 ¶ 5, Supplemental Figure S1A].
Regarding claim 3-4 and 32, as discussed above, Kambara discloses wherein the MRC1 promoter drives transgene expression in liver and splenic MCR1+ macrophages [column 3 ¶ 3-column 4 ¶ 3, column 8 ¶ 3, Figure 1C].
Regarding claims 8-9, note that claims 8-9 as written further limit an option of claim 2 without requiring the inclusion of that option. Therefore, claims 8 and 9 are required limitations of the invention only when the option of claim 2(b) one or more miRNA target sequences is the selected option. Accordingly, claims 8-9 encompass wherein an alternative option of claim 2 is present in the invention without the further limitations introduced by claims 8 and 9. As such, by teaching the limitations of claims 1 and 2 disclosing an invention wherein the vector comprises 2(a) a phagocyte-specific promoter, He, Kambara, Zhang, and Zhu teach an invention which encompasses claims 8 and 9 in that claims 8-9 add no further limitations to the invention.
Further regarding claims 8-9, Geisler teaches that miRNA-dependent post-transcriptional suppression of transgene expression has been emerging as powerful new technology to increase the specificity of vector-mediated transgene expression [column 2 ¶ 1]. Geisler additionally teaches that to control exogenous transgene expression, tandem repeats of artificial miRNA target sites are usually incorporated into the 3’ UTR of the transgene expression cassette, leading to subsequent degradation of transgene mRNA in cells expression the corresponding miRNA, wherein the targeting strategy, which was first shown for lentiviral vectors in antigen presenting cells, has not been used for tissue-specific expression of vector-encoded therapeutic transgenes to reduce immune response against the transgene, to control virus tropism for oncolytic virotherapy, to increase safety of live attenuated virus vaccines, and to identify and select cell subsets for pluripotent stem cell therapies [column 12 ¶ 1].
Geisler further teaches that miR-122 is a miRNA almost exclusively expressed in liver tissue and represents the best candidate for a specific hepatocyte-de-targeting, such that successful miR-122-mediated suppression of transgene expression in liver was found in several studies [column 6 ¶ 2, Table 1]. Geisler teaches that miR-122 has specifically been used in a metastatic HCC model to de-target hepatocytes for expression of an AAV8-delivered HSV thymidine kinase and luciferase transgenes [Table 1].
Geisler also teaches that miR-124 has been successfully used to de-target lentivirally delivered Interferon-α (IFN-α) away from hematopoietic stem and progenitor cells to target tumor-infiltrating macrophages, thereby inhibiting breast cancer progression [column 16 ¶ 2-column 17 ¶ 1, Table 1].
Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to include target sites for miRNAs, in a transgene expression vector to reduce expression in non-targeted cells, and particularly to use miR-122 and/or miR-126 target sequences reduce hepatocyte and HSC expression of transgenes targeting tumor infiltrating macrophages in HCC.
Regarding claim 12-13, He, Kambara, Zhang, and Zhu teach the limitations of claim 1, including the motivation to target TAMs in an HCC tumor to modulate TAM secretion and reduce tumor growth, invasiveness, and metastasis. He, Kambara, Zhang, and Zhu do not specifically teach that the transgene to deliver is a cytokine, a tumor antigen, or specifically IFN-α.
As discussed above, Geisler teaches that miR-124 has been used successfully to de-target lentivirally delivered interferon-α (IFN-α) away from hematopoietic stem and progenitor cells to target IFN-α expression in tumor-infiltrating macrophages, thereby inhibiting breast cancer progression [column 16 ¶ 2-column 17 ¶ 1, Table 1].
Geisler does not teach motivation to specifically deliver IFN-α to tumor-infiltrating macrophages within the liver.
However, De Palma teaches that that type I IFNS, including IFN-α, increase tumor immunogenicity, recruit and activate immune cells within the tumor milieu, and may eventually facilitate tumor rejection [column 3 ¶ 1]. De Palma also teaches delivering tumor-homing proangiogenic, tumor-infiltrating Tie2-expressing monocytes (TEMs) genetically modified to express IFN-α, which achieved substantial antitumor activity in both prevention and intervention trials without measurable toxicity [abstract, column 1 ¶ 1- column 2 ¶ 2, column 3 ¶ 2, SIGNIFICANCE box]. De Palma further teaches that their experiments illustrate the therapeutic potential of gene- and cell-based IFN-α delivery and should allow the development of IFN treatments that more effectively treat cancer [abstract].
Therefore, given the teachings of Geisler of delivering IFN-α to tumor infiltrating macrophages; the teachings of De Palma to modify tumor-infiltrating monocytes to secrete IFN-α to selectively deliver the IFN-α to tumors; and the teaching of Zhang discussed above that tumor-associated macrophages (TAMs) are recruited in the monocyte precursor form from the peripheral blood; an ordinarily skilled artisan at the time of filing the instant application would be motivated to modify tumor infiltrating monocytes/macrophages to express an IFN-α transgene, thereby secreting IFN-α within a tumor as a means to selectively deliver the antitumor IFN-α to tumors to facilitate tumor rejection.
Regarding claims 17-18, He, Kambara, Zhang, and Zhu teach the limitations of claim 1.
Additionally, Geisler teaches that miR-124 has been used successfully to de-target lentivirally delivered interferon-α (IFN-α) away from hematopoietic stem and progenitor cells to target IFN-α expression in tumor-infiltrating macrophages, thereby inhibiting breast cancer progression [column 16 ¶ 2-column 17 ¶ 1, Table 1]. De Palma teaches the delivery of the IFN-α transgene to the TEMs in a lentiviral vector (LVs) regulated by the phagocyte-specific Tie2 promoter/enhancer [column 3 ¶ 2, column 20 ¶ 4]. De Palma further teaches that by intravenous injection, LVs preferentially transduce the liver and spleen [column 8 ¶ 2].
Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to deliver a transgene, such as IFN-α, for macrophage-specific expression in the liver and/or spleen by using a lentiviral vector to achieve preferential transduction of the liver and spleen.
Regarding claims 22, He, Kambara, Zhang, and Zhu teach the limitations of claim 1. He further teaches that MRC1 is a prototypical M2-type marker in human macrophages [column 6 ¶ 5]. Kambara also teaches that Mrc1 is an M2 phenotypic marker [column 3 ¶ 3]. Zhang teaches that M2 macrophages specifically express CD206/MRC1 [column 3 ¶ 2]. Zhu teaches that CD206/MRC1 expression is correlated with the alternatively activated (M2) polarization of macrophages [column 2 ¶ 4].
De Palma teaches that lentivirus preferentially transduces liver and spleen [column 8 ¶ 2].
Additionally, Geisler teaches that cell specificity can be further enhanced by incorporating miRNA target sequences into transgene vectors, including incorporation of target sites for miR-126 to de-target HSCs to facilitating specific targeting of tumor-infiltrating macrophages and miR-122 to de-target hepatocytes in an HCC model [Table 1].
Therefore, given the teachings of He, Kambara, Zhang, and Zhu that MRC1 expression/ MRC1 promoter activity is specific to macrophages, the teaching of De Palma that lentivirus preferentially transduces liver and spleen, and the teachings of Geisler to incorporate miRNA target sites to de-target hepatocytes and HSCs, an ordinarily skilled artisan at the time of filing the instant application would expect the transduced vector to express the transgene specifically in MCR1+ macrophages without substantial expression in other cells.
Regarding claims 23, He, Kambara, Zhang, and Zhu teach the limitations of claim 1. Kambara also teaches substantially higher expression from the native MRC1 promoter in macrophages of the lung, liver, and spleen compared to the kidney [Figure 1]. Zhu teaches that CD206/MRC1 was highly expressed in the HCC tissues compared to the level in peri-carcinoma tissue [abstract, column 3 ¶ 4, column 6 ¶ 6- column 7 ¶ ].
De Palma teaches that lentivirus preferentially transduces liver and spleen [column 8 ¶ 2].
Therefore, given the teachings of Kambara that the MRC1 promoter drives expression selectively in lung, liver, and spleen; the teaching of Zhu that MRC1 expression is particularly high within HCC tumors; and the teaching of De Palma that lentivirus preferentially transduces liver and spleen; an ordinarily skilled artisan at the time of filing the instant application would expect the vector to express the transgene specifically in liver cells and/or splenic cells without substantial expression in other cells.
Regarding claim 24, He teaches a cell comprising the MCR1-luc vector [column 4 ¶ 3].
Given the motivation taught by Kambara, Zhang, and Zhu to target TAMs in an HCC tumor to modulate TAM secretion and reduce tumor growth, invasiveness, and metastasis; the motivation taught by Geisler to include miR-122 and/or miR-126 target sequences to reduce hepatocyte and HSC expression of transgenes targeting tumor infiltrating macrophages in HCC; the motivation taught by Geisler, De Palma, and Zhang to modify tumor infiltrating macrophages to express an IFN-α transgene to selectively deliver the antitumor IFN-α to tumors; the motivation taught by Geisler and De Palma to deliver a IFN-α transgene for macrophage-specific expression in the liver and/or spleen by using a lentiviral vector to achieve preferential transduction of the liver and spleen; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the vector of He to replace the luciferase transgene with a transgene encoding IFN-α, to include target sites for miR-122 and/or miR-126 to de-target hepatocytes and/or HSCs, and to package the transgene expression cassette in a lentiviral vector for specific expression in tumor-infiltrating macrophages within the liver and/or spleen to treat a tumor such as HCC with a reasonable expectation of success.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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