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 .
Claim status
Claims 1-20 filed on August 11, 2023 are pending and will be examined on the merits.
Priority
The instant application claims benefit of a provisional application, Application No. 63397666 (filed 12 August, 2022). The effective filing date of instant claims 1-20 is 12 August, 2022.
Information Disclosure Statement
The information disclosure statement filed on May 31, 2024 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, each information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because:
The instant application file contains at least one drawing executed in color (See 020269-US-NP_2023-08-11_Figures filed on 8/11/2023). A petition was filed under 37 CFR 1.84(a)(2) on 8/11/2023, which was dismissed by the office on 11/01/2023.
Figure 1 shows a schematic of experimental workflow in accordance with the present disclosure, the annotation for the Choroid dataset by AP Voift et al (2022) was incomplete, therefore, unreadable.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
On page 3, regarding “Description of the Drawings”, row 10 recites, “FIG. 2A-FIG. 2B is an exemplary embodiment showing “cell heterogeneity of circulating immune cells and choroid” in accordance with the present disclosure. FIG. 2A is a UMAP plot showing cell type heterogeneity of PBMCs. FIG. 2B is a dot plot showing marker gene expression for cell types in PBMCs.” Based on the examiner’s interpretation of the data, these figures do not contain information regarding choroid, therefore the description is not accurate.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 20 is 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 20 recites “the method of claim 1, wherein administering the CYR61 activating agent to the subject results in at least one of: upregulating endothelial cell expression of one or more genes selected from the group consisting of CCL2, CXCL6, CXCL1, TFRC, IL32, and combinations thereof; and downregulating endothelial cell expression of one or more genes selected from the group consisting of LYVE1, DEPP1, FCF1, AC020916.1, LINC02603, and combinations thereof.” The limitation “administering the CYR61 activating agent to the subject” is not mentioned in the method recited in claim 1. The method recited in claim 1 comprises administering a CYR61 activating agent to an immune cell, not to a subject directly. Therefore, there is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 103
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 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 1-10, 20 are rejected under 35 U.S.C. 103 as being unpatentable over Apte et al. "Macrophages inhibit neovascularization in a murine model of age-related macular degeneration." PLoS medicine 3.8 (2006): e310, in view of Bai et al. "Matricellular protein CCN1 activates a proinflammatory genetic program in murine macrophages." The Journal of immunology 184.6 (2010): 3223-3232, as evidenced by Sorgi et al. "GM-CSF priming drives bone marrow-derived macrophages to a pro-inflammatory pattern and downmodulates PGE2 in response to TLR2 ligands." PloS one 7.7 (2012): e40523.
Claim 1 recites a method of treating ocular neovascularization in a subject, the method comprising: administering a CYR61 activating agent to an immune cell to form a treated immune cell; and administering the treated immune cell to the subject.
Apte et al (2006) teach in a laser induced choroidal neovascularization (CNV) mouse model, which is a surrogate acute injury model for age related macular degeneration (AMD), injection of GM-CSF stimulated macrophages (CD11b+ cells) obtained from bone marrow culture in the presence of GM-CSF (page 1373, column 1, “Bone Marrow Culture”) into the vitreous cavity at the time of laser treatment significantly reduced CNV (page 1375, column 1, paragraph 1, Figure 4A). Similarly, intravitreal injection of cultured CD11b+ cells obtained from spleen reduced CNV, whereas T cells (CD3+) and CD11c+ (dendritic cells) had no effect on the size of CNV lesion (page 1375, column 1, paragraph 1, Figure 4B).
As evidenced by Sorgi et al (2012), bone marrow derived macrophages (BMDM) from WT mice were primed with GM-CSF for 24 h and then incubated for 24 h with TLR2 and TLR4 agonists (page 2, column 1, paragraph 1), compare with unprimed BMDM, these GM-CSF primed macrophages produced increased amount of TNFa in a dose dependent manner (page 4, Figure 2). Similarly, these GM-CSF primed BMDMs exhibit strong NFkB activation upon TLR agonist stimulation (Figure 8A-C). Since both TNFa and NFkB play central role in pro-inflammatory immunity, these data suggest that GM-CSF primed BMDM have an activated, pro-inflammatory M1-like phenotype.
Apte et al (2006) depicts that IL-10 deficient mice, which have increased inflammation in response to diverse stimuli due to the immune-suppressive effect of IL-10, have significantly reduced (CNV) lesion compared to wild type B6 mice upon laser induction of CNV (Figure 1). This is accompanied by increased macrophage infiltrates in the eye of IL-10 deficient mice (page 1374, column 1, paragraph 5, column 2, paragraph 1, Figure 2A-D) compared to B6 mice. Apte et al further demonstrated that depletion of macrophages by antibodies anti-CD11b and anti-F4/80 or intravitreal injection of IL-10, increased the level of CNV lesion (page 1374, column 2, paragraph 2-3), suggesting that inflammatory macrophages inhibits angiogenesis in the retina in the AMD mouse model.
However, Apte et al (2006) do not teach a method of using CYR61 to treat an immune cell.
Using mouse macrophage cell lines RAW264.7 and I-13.35, and freshly isolated peritoneal macrophages from wild-type C57BL/6 mice, Bai et al (2010) demonstrated a general role of CYR61 in regulating inflammatory genes (Figure 4A-D, page 3226, column 2, paragraph 1; page 3227, column 1, paragraph 1; page 3229, column 1, paragraph 3, column 2, paragraph 1). Bai et al teach that CCN1 (CYR61) supports the adhesion of macrophages through integrin aMb2 and syndecan-4, activates NFkB-mediated transcription, and induces a proinflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNF-a, IL-1a, IL-1b, IL-6, and IL-12b), chemokines (MIP-1a; MCP-3; growth-related oncogenes 1 and 2; and inflammatory protein 10), and regulators of oxidative stress and complement (inducible NO synthase and C3) and downregulation of specific receptors (TLR4 and IL-10Rb) and anti-inflammatory factors (TGF-b1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NF-kB by CCN1, leading to the synthesis of cytokines including TNF-a and inflammatory protein 10; and a delayed response resulting from CCN1-induced TNFa, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1b and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates proinflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation (Abstract, Figures 2-5).
Given the strong effect of CYR61 in activating proinflammatory genes and increasing their expression taught by Bai et al (2010) and that intravitreal administration of activated, proinflammatory macrophage can effectively reduce CNV lesion in the AMD mouse model as taught by Apte et al (2006), one with ordinary skill in the art would be motivated to use CYR61 to treat a macrophage, such as BMDM, to induce a proinflammatory activation state in these cells, and administer the activated BMDM intravitreally to an AMD mouse model and expect the treatment to reduce CNV lesions. This method meets the limitations in claims 1, 2, 3, 4, 5, 6, 7, and 9.
Regarding claims 10 and 20, Bai et al (2010) recites cytokine IL-1b, complement C3, and growth related oncogenes 1, which is equivalent to CXCL1, are upregulated by CYR61 in treated macrophages. These data meets the limitations in claims 10 and 20.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Apte et al, in view of Bai et al (2010), as evidenced by Sorgi et al (2012), in further view of Tan et al. "Neovascular age-related macular degeneration (nAMD): a review of emerging treatment options." Clinical Ophthalmology (2022): 917-933.
Claim 8 recites the method of claim 1, further comprising administering to the subject an anti-VEGF treatment. It is well known in the art that anti-VEGF treatment is FDA approved therapy for AMD, they reduce pathologic ocular neovascularization by blocking VEGF signaling pathway. As taught by Tan et al (2022), “Vascular endothelial growth factor (VEGF) is a potent endothelial-specific mitogen that elicits angiogenesis and vascular hyperpermeability in response to hypoxia. VEGF is involved in the pathogenesis of AMD, with increased expression of VEGF reported in the RPE and vitreous of eyes with both non-neovascular and neovascular AMD. Anti-vascular endothelial growth factor (anti-VEGF) agents are medications aimed at blocking the effects of VEGF. The introduction of these agents have revolutionized the treatment of AMD. In clinical trials, patients treated with intravitreal anti-VEGF agents experienced gains in best-corrected visual acuity.” (page 917, paragraph 3-4; page 918, paragraph 1) However, “the frequency of injection of anti-VEGF drugs and requirement for long-term treatment present significant financial and logistical burdens on both patients and healthcare system.” (page 931, paragraph 2).
Since CYR61 treatment activates macrophages which could effectively control the CNV lesion as discussed above, while anti-VEGF is an FDA approved treatment of AMD that blocks endothelial cell angiogenesis, as taught by Tan et al (2022), a person with ordinary skill in the art would have been motivated to combine the CYR61 treated macrophage therapy with an anti-VEGF therapy with distinct mechanisms of action to achieve enhanced inhibition of CNV disease lesion in AMD with a reasonable expectation of success. This combination therapy may allow less frequent treatment and/or lower dose of anti-VEGR therapy, which helps to alleviate the financial and logistical burdens associated with anti-VEGF treatments.
Claims 11-19 are rejected under 35 U.S.C. 103 as being unpatentable over Apte et al (2006), in view of Bai et al (2010), and in further view of Hasan et al. "The matricellular protein cysteine-rich protein 61 (CCN1/Cyr61) enhances physiological adaptation of retinal vessels and reduces pathological neovascularization associated with ischemic retinopathy." Journal of Biological Chemistry 286.11 (2011): 9542-9554, and as evidenced by Droho et al. "Ocular macrophage origin and heterogeneity during steady state and experimental choroidal neovascularization." Journal of neuroinflammation 17.1 (2020): 341.
Claim 11 recites a method of activating an immune cell in a subject, the method comprising administering to the subject a CYR61 activating agent.
The teaching of Apte et al (2006) and Bai et al (2010) on the effect of CYR61 on macrophages and the effectiveness of CYR6 activated macrophages in treating a macular degeneration disease are discussed above.
Apte et al (2006) teach that IL-10 deficient mice have significantly reduced (CNV) lesion compared to wild type B6 mice upon laser induction of CNV and activated macrophages in these mice due to lack of immune-suppressive IL-10 are responsible for the inhibition of CNV lesion. Apte et al further teach that when IL-10 is inhibited by anti-IL-10 systemic delivery into wild type B6 mice, the CNV lesion induced by laser is significantly reduced (Figure 1B). These data suggest that endogenous macrophages in the mouse model can be activated and these activated macrophages can inhibit CNV lesion.
However, Apte et al (2006) do not teach direct administration of a macrophage activating agent, such as CYR61, as taught by Bai et al (2010), into the eye of the AMD model to treat the CNV lesion.
Hasan et al (2011) depict a method of using in situ expression of CYR61 to treat pathological angiogenesis associated with oxygen-induced retinopathy (OIR) in mice, a mouse model for retinopathy of prematurity (ROP) which is characterized by disrupted angiogenesis and vasculogenesis in the hyperoxia induced vas-obliteration phase and ischemia-induced neovessel formation phase. Hasan et al showed that lentivirus-mediated expression of CCN1 enhanced physiological adaptation of the retinal vasculature to hyperoxia and reduced pathological angiogenesis following ischemia (Abstract). When Lnv-CCN1 and control LnV-Luc was injected into the vitreous in one eye of mice pups subjected to OIR, at P12, an extensive vaso-obliteration was clearly evident in retinas from Lnv-Luc-injected control eyes, whereas retinas from Lnv-CCN1-injected eyes showed normally formed blood vessels over a considerably wider area of the central region (Fig. 2A). Quantitative analyses showed that more than 70% of the retinal surface was vascularized in Lnv-CCN1-injected eyes but less than 60% was vascularized in Lnv-Luc-injected eyes (Fig. 2C). At P17, the retinal vasculature in eyes injected with Lnv-CCN1 exhibited normal morphology and branching in the midperipheral and peripheral regions except for spares areas around the central retina (Fig. 2B). Quantitative analyses showed that retinal vessels extended over 68 and 78% of the retinal surface in Lnv-Luc- and Lnv-CCN1-injected eyes, respectively (Fig. 2C). Preretinal neovascular tufts, which can be seen abundantly in the central and midperipheral retina in Lnv-Luc-injected eyes, were minimally present in eyes injected with the Lnv-CCN1 vector (Fig. 2D). Similarly, the number of preretinal nuclei significantly decreased in eyes injected with CCN1 vector as compared with those injected with a control vector (Fig. 2E). These data demonstrated that ectopic expression of the CCN1 reduced ischemia and subsequently, suppressed preretinal neovascularization, allowing development of stable retinal blood vessels following vaso-obliteration in the OIR model (page 9550, column 2, paragraph 3).
Although the pathological neovascularization in ROP and AMD differ in the origin: ROP involves neovascularization growing from the retina into the vitreous in infants, while AMD features choroidal vessels growing into the subretinal in the elderly, the fact that ectopic expression of CNN1 (CYR61) intravitreally can effectively reduce ischema and suppress preretinal neovascularization suggest the intravitreal administration of active CYR61 is feasible. Since ocular macrophages including resident microglial and macrophages, as well as monocyte derived macrophages are present in retina, drainage structure and vitreous, as evidenced by Droho et al (2020) (Figure 8), intravitreally administered CYR61 would enable direct interaction with ocular macrophages and activate them into a proinflammatory, M1 polarized state, as taught by Bai et al (2010).
Therefore, it would have been obvious for a person with ordinary skill in the art to administer CYR61 using a lentiviral expression vector, as taught by Hasan et al (2011), intravitreally into the laser induced choroidal neovascularization mouse model, as taught by Apte et al (2006), and expect CYR61 activation of ocular macrophages into a proinflammatory state, which allow them to upregulate expression of immune factors including C3 and IL1b, as taught by Bai et al (2010), and expect reduction of of CNV lesions. This method meets the limitation of claims 11, 12, 13, 14, 15, 16, 18, and 19.
Regarding claim 17 which recites the method of claim 11, further comprising administering to the subject at least one of an anti-VEGF treatment and a photodynamic therapy, since it is well known in the art that anti-VEGF treatment and photodynamic therapy are FDA approved therapy for AMD, a person with ordinary skill in the art would have been motivated to combine the CYR61 treated macrophage therapy discussed above with these FDA approved therapies to achieve enhanced inhibition of CNV disease lesion in AMD with a reasonable expectation of success.
Conclusion
All claims are rejected.
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/HONG REN/
Examiner, Art Unit 1647
/JOANNE HAMA/ Supervisory Patent Examiner, Art Unit 1647
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