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 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
The instant application, filed 04/13/2023, is a 371 filing of PCT/US21/55028, filed 10/14/2021, and claims domestic benefit to US provisional application 63/091,558, filed 10/14/2020.
Status of Application, Amendments, and/or Claims
Applicant’s response filed 05/12/2026 is acknowledged. Claims 1-4, 6, 9-10, and 16 are amended; claims 11-12 and 18-20 are cancelled; and claims 21-23 are new. Claims 1-10, 13-17, and 21-23 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 02/12/2026, the sequence incorporation by reference paragraph was objected to. Applicant’s amendment to the specification to recite the size of the sequence listing in bytes has overcome the objection and the objection is withdrawn.
The drawings were objected to for being low resolution. Applicant’s submission of supplemental drawings has overcome the objection and the objection is withdrawn
Claims 2-3 and 11 were rejected under 35 USC 112(b). Applicant’s amendment to claim 2 to remove the limitation in parenthesis and the cancellation of claim 11 has overcome the rejections and the rejections are withdrawn.
Claims 1-9 and 15 were rejected under 35 USC 103 over US’898. Applicant’s amendment to independent claims 1 and 6 to recite that the methods reduce cardiomyocyte death has overcome the rejections and the rejections are withdrawn.
Claims 1-12 and 15 were rejected under 35 USC 103 over US’484, Lutter, and US’898. Applicant’s amendment to independent claims 1 and 6 to recite that the methods reduce cardiomyocyte death has overcome the rejections and the rejections are withdrawn.
Claim 13 was rejected under 35 USC 103 over US’484, Lutter, US’898, and WO’304. Applicant’s amendment to independent claim 1 to recite that the method reduces cardiomyocyte death has overcome the rejection and the rejection is withdrawn.
Claims 14 and 18-20 were rejected under 35 USC 103 over US’484, Lutter, US’898, and Serpooshan. Applicant’s amendment to independent claim 1 to recite that the method reduces cardiomyocyte death and the cancellation of claims 18-20 has overcome the rejections and the rejections are withdrawn.
Claim 16 was rejected under 35 USC 103 over Serpooshan, US’484, Lutter, and US’898; and claim 17 was rejected under 35 USC 103 over Serpooshan, US’484, Lutter, US’898, and WO’304 Applicant’s amendment to independent claim 16 to recite limitations concerning the amount of reelin polypeptide in the collagen patch has overcome the rejections and the rejections are withdrawn.
The following grounds of objections and/or rejections are new as necessitated by applicant’s amendment to the claims.
Drawings
The supplemental drawings filed 05/12/2026 are objected to for containing colored drawings without an appropriate petition filed under 37 CFR 1.84(a)(2). A petition for colored drawings or black and white/grayscale images are required.
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, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
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).
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.
Claims 1-10, 15, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Huang, L.H., et al (2017) Cardiac Lymphatic vessels, transport, and healing of the infarcted heart JACC: Basic to translational science 2(4); 477-483 in view of US 9,486,484 B2 (Alfonso, Z. and J.K. Fraser) 8 Nov 2016, Lutter, S., et al (2012) Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation J. Cell. Biol. 197(6); 837-849 and US 2003/0219898 A1 (Sugaya, K., et al) 27 Nov. 2003.
Huang teaches that the lymphatic vasculature plays a key role in regulating tissue fluid homeostasis, lipid transport, and immune surveillance throughout the body. Although it has been appreciated that the heart relies on lymphatic vessels to maintain fluid balance and that such balance must be tightly maintained to allow for normal cardiac output, it has only recently come to light that the lymphatic vasculature may serve as a therapeutic target with which to promote optimal healing following myocardial ischemia and infarction. Huang provides a review of cardiac lymphatic vessels and highlights studies that imply targeting of lymphatic vessel development or transport using VEGF-C may serve as a promising avenue for future clinical application in the context of ischemic injury (abstract).
Huang teaches that myocardial ischemia, the lack of blood supply to the heart, causes rapid death of cardiac myocytes. At the same time, fluid accumulates in the cardiac interstitial space, leading to formation of myocardial edema due to increased myocardial microvascular permeability and the filtration rate exceeding the lymph flow rate. Although resultant fibrotic tissue can compensate for the loss of cardiomyocytes and provide structural support following myocardial infarction to protect against cardiac rupture, myocardial fibrosis also has negative consequences such as hindering interstitial fluid drainage, impairing cardiac function, and contributing to adverse ventricular remodeling. Intriguingly, lymphatic drainage through the myocardium can be recovered by remodeling collateral circulation. This alleviates inflammatory response orchestrated by chemokines and recruits leukocytes elicited following ischemic tissue injury (paragraph bridging pages 480-481).
Huang concludes that recent studies in the field had introduced the possibility that heart conditions, such as ischemia and infarction, may be treated by direct targeting of the lymphatic vasculature. In particular, the therapeutic administration of VEGF-C in 2 different studies improved the rate and quality of cardiac healing in experimental myocardial infarction in mice and rats. The positive outcome may be attributed to increased lymphangiogenesis of lymphatic capillaries in the heart but may otherwise also relate to sustained functionality of the deeper lymphatic collecting vessels (paragraph bridging columns, page 482).
As discussed above, Huang teaches the treatment of cardiac ischemia and infarction by targeting of the lymphatic vasculature and also teaches that ischemia causes rapid death of cardiac myocytes. These teachings suggest that, by treating ischemia, the death of cardiac myocytes would be reduced. Huang; however, does not teach that the therapeutic targeting the lymphatic vasculature is a reelin polypeptide or a variant thereof.
US’484 teaches methods of treating a disease or disorder selected from a group that includes cardiovascular disease and heart disease comprising administering an isolated population of adipose derived cells comprising lymphatic endothelial cells (LECs) and pre-LECs (col. 12, lines 18-36). US’484 further teaches that the importance of molecules including hyaluronan, integrins, reelin, IL-7, and matrix metalloproteinases in LEC growth, migration, tube formation, and survival have been reported. In some embodiments, one or more of these molecules is used to enhance or modify the activity of the cells by co-administration (page 62, lines 48-61).
US’484 teaches that the lymphatic system plays a dual role in fluid transport and immune surveillance. In fluid transport, extravasated fluid and macromolecules pass into lymphatic vessels that are lined by a single layer of lymphatic endothelial cells (LECs) surrounded by an incomplete basement membrane. Fluid is transferred from these vessels into larger vessels, many of which are lined by lymphatic smooth muscles that exhibit spontaneous beating, which, in concert with the action of adjacent skeletal muscle, pumps the lymph fluid back to the venous system through the thoracic duct (col. 1, lines 39-50).
A number of pathological conditions exist in which the ability of the lymphatic system to transport fluid is insufficient to meet demand. This leads to tissue edema that is disfiguring, disabling, and, on occasion, life threatening. There are, thus, a number of settings in which modulation of expansion or repair of the lymphatic system are clinically desirable. Acute myocardial infarction leads to increased vascular permeability, thereby increasing the amount of fluid and macromolecules in the interstitial space for removal by the lymphatic system. This edema leads to tissue injury throughout the ventricle, causing histologically visible gaps between vascular endothelial cells and activation of platelets that reduce blood vessel patency. Myocardial edema is evident in many clinical states and can be caused or worsened by cardiac surgery and myocardial infarction. The consequences of edema have been studied in animal models of chronic lymphatic obstruction. These studies indicate myofibrillar disruption resulting from edema-induced separation of cardiac monocytes and formation of non-elastic scar tissue which can, in turn, lead to impaired conductance and arrythmia (col. 2, lines 23-48).
US’484 further teaches that myocardial edema can result in comprised cardiac function. Causes of myocardial edema include cardiac surgery, as well as myocardial ischemia, arterial or pulmonary hypertension, and cardiac transplant. The methods taught can be used to increase lymphatic function either directly, e.g. through cell engraftment, or indirectly, e.g., by secreting factors that stimulate growth or activity of the existing lymphatic system. Secreted factors can act on host cells and/or cells administered according to the methods disclosed (col. 70, lines 21-27).
US’484 teaches that treatment includes reducing or alleviating at least one adverse effect or symptom of a lymphatic system condition, disease, or disorder, i.e., any disorder characterized by abnormal, anomalous, or insufficient lymphatic function (col. 19, lines 19-26).
US’484 further teaches compositions that include collagen matrix or support (col. 61, lines 26-27, and teaches that the composition can be for surgical implantation at a particular site (col. 61, lines 64-65).
Lutter teaches that active lymph transport relies on smooth muscle cell (SMC) contractions around collecting lymphatic vessels. Lutter identifies reelin, an extracellular matrix glycoprotein previously implicated in central nervous system development, as a an important regulator of lymphatic vascular development (abstract). Reelin is identified as a lymphatic-specific matrix molecule and demonstrates its important function in the formation of functional collecting lymphatic vessels. In addition, Lutter teaches a unique mechanism by which reelin signaling is activated via communication between the two cell types that form the collecting vessels: endothelial and smooth muscle cells (SMCs). The specific defects displayed by Reln-deficient mice further highlight a hitherto unrecognized important function of SMCs in lymphatic vessel morphogenesis and function (page 838, left column, paragraph 2).
Lutter also analyzed reelin expression and secretion by lymphatic ECs (LECs ) cultured alone or together with SMCs and teaches that LECs produce reelin protein (paragraph bridging pages 840-841). Lutter further teaches that reelin acts in an autocrine fashion in LECs to induce production of SMC recruitment factors and teaches a transient increase in regulators of SMC recruitment and migration in LECs upon reelin stimulation (page 844, left column, paragraph 1).
US’898 teaches methods of treating neurological or corporal deficits without the problems associated with heterologous transplants from adult or fetal sources (page 8, [0075]). US’898 teaches that corporal deficits are a target for amelioration and refers to a disorder caused by a wide variety of diseases including trauma, malfunction, degeneration or loss of muscle such as, for example, cardiac muscle due to myocardial infarction (page 3, [0022]; page 16, [0152]-[0153]). US’898 teaches that injuries that can be treated according to the methods disclosed include ischemia and injuries caused by a stroke, including a global stroke, as may be caused by cardiac arrest, arrhythmia, or myocardial infarction (page 15, [0140]).
US’898 teaches methods of altering the migration and/or differentiation of endogenous or exogenous multipotent stem cells in a mammal by modulating the levels of APP and/or reelin in the mammal. US’898 teaches an embodiment in which the amount of reelin in a mammal is altered by administration of reelin protein (page 5, [0035]).
US’898 teaches that reelin is a large extracellular matrix protein of approximately 400 kDa and that it has been found that reelin plays an important role in regulation of NSC biology. The addition of recombinant reelin to NSCs in culture increased mobility of cells in the cluster of cells that typified their growth. When NSCs were transplanted in the brain of reeler homozygous mice that do not express reelin, migration was nearly halted. It was found that only cells expressing reelin migrated into the cortex of reeler homozygous mice. These results suggest that reelin is an indispensable factor for the migration of NSCs or more developmentally potent cells (pages 16-17, [0158])-[0159]).
Mammals with suppressed reelin expression may not experience proper migration of endogenous or exogenous multipotent cells. The reelin protein can be administered to a mammal in need. For example, reelin can be introduced at the site of a stroke to encourage the migration of multipotent cells into the area of damage to start repair (page 17, [0160]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by Huang by substituting the therapeutic targeting the lymphatic vasculature, such as VEGF-C, with reelin based on the teachings of US’484, Lutter, and US’898. It would have further been obvious to administer a reelin polypeptide, including a recombinant reelin polypeptide, based on the teachings of US’898.
An ordinarily skilled artisan would have been motivated to use reelin to treat cardiac ischemia and infarction thereby reducing cardiomyocyte death as US’484 teaches that the importance of reelin has been identified in LEC growth, migration, tube formation, and survival. The selection of reelin is further motivated by Lutter which demonstrates that reelin is important in regulating the formation of functional lymphatic vessels and is involved in a signaling pathway between LECs and SMCs. US’898 also motivates the use of reelin teaching that reelin protein can be administered to heart related conditions to encourage migration of multipotent cells into the area of damage to start repair. An ordinarily skilled artisan would have had a reasonable expectation of success as Huang teaches the use of therapeutics targeting the lymphatic vasculature and both US’484 and Lutter teach the importance of feeling in the formation of lymphatic vessels. Additionally, US’484 and US’898 teach methods of treating diseases or conditions of the heart using reelin. It would have further been obvious to administer a reelin polypeptide, including a recombinant reelin polypeptide, as the administration of a reelin protein is taught by US’898 as a means to treat heart related conditions. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
It is further noted that, while one of ordinary skill in the art would reasonably expect that by treating ischemia the death of cardiac myocytes would be reduced based on the teachings of Huang, the function of reducing cardiac myocytes would flow naturally, and mechanistically, from following the suggestions of the prior art. That is to say that, by treating ischemia with a therapeutic targeting the lymphatic vasculature, such as reelin, the death of cardiac myocytes would naturally be reduced.
MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Regarding claims 4-5, and 9, while the combination of Huang, US’484, Lutter, and US’898 do not experimentally demonstrate the claimed outcomes, such outcomes would have been expected in view of the teachings of the combination of applied references. For instance, as discussed in detail above US’484 teaches methods for the improvement of cardiac lymphatics and a reduction in fluid accumulation following cardiac conditions, including myocardial infarction, by administration of reelin. US’898 teaches the amelioration of corporal defects, including ischemia, stroke, cardiac arrest, arrhythmia, or myocardial infarction. As the combination of Huang, US’484, Lutter, and US’898 teach that the disclosed defects/conditions are treated with reelin, an ordinarily skilled artisan would reasonably expect that the defects/conditions disclosed would be alleviated sooner than untreated controls and would be a measurable improvement.
Additionally, the outcomes recited would flow naturally, and mechanistically, from following the teachings of the combination of Huang, US’484, Lutter, and US’898 in which reelin is administered to patients with the disclosed conditions. See MPEP 2145 II.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Huang, L.H., et al (2017) Cardiac Lymphatic vessels, transport, and healing of the infarcted heart JACC: Basic to translational science 2(4); 477-483, in view of US 9,486,484 B2 (Alfonso, Z. and J.K. Fraser) 8 Nov 2016, Lutter, S., et al (2012) Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation J. Cell. Biol. 197(6); 837-849 and US 2003/0219898 A1 (Sugaya, K., et al) 27 Nov. 2003 as applied to claim 1 above, and in further view of WO 2011/091304 A1 (Watts, R.J., et al) 28 July 2011.
The combination of Huang, US’484, Lutter, and US’898 teach the method of claim 1 as discussed in detail above.
The combination of applied references, however, do not expressly disclose that the reelin polypeptide comprises SEQ ID NO: 1 or a fragment thereof.
WO’304 teaches that the amino acid sequence of naturally occurring human reelin is presented in SEQ ID NO: 3, from Genbank AAC51105.1 (page 16, line 14 – page 18, line 13). WO’304 teaches administration of reelin as a shuttle agent that binds to LRP8 and also teaches that fragments of human reelin can be used that maintain binding to the receptor (page 81, claim 5). WO’304, SEQ ID NO: 3 is identical to instant SEQ ID NO: 1. Alignment identity from ABSS is shown below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the human reelin polypeptide sequence disclosed by WO’304 in the method disclosed by the combination of Huang, US’484, Lutter, and US’898. It would have been obvious to an ordinarily skilled artisan to use polypeptide sequence disclosed by WO’304 as it is the art recognized sequence of human reelin which is the protein that is taught by the combination of Huang, US’484, Lutter, and US’898. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. The expectation of success is further supported by WO’304 which demonstrates that administration of reelin with the recited sequence to patients had been considered in the art.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Huang, L.H., et al (2017) Cardiac Lymphatic vessels, transport, and healing of the infarcted heart JACC: Basic to translational science 2(4); 477-483 in view of US 9,486,484 B2 (Alfonso, Z. and J.K. Fraser) 8 Nov 2016, Lutter, S., et al (2012) Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation J. Cell. Biol. 197(6); 837-849 and US 2003/0219898 A1 (Sugaya, K., et al) 27 Nov. 2003 as applied to claim 1 above, and in further view of Serpooshan, V., et al (2013) The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function post myocardial infarction Biomaterials 34(36); 1-15.
The combination of Huang, US’484, Lutter, and US’898 teach the method of claim 1 as discussed in detail above.
As discussed above, US’484 teaches compositions that include collagen matrix or support (col. 61, lines 26-27), and teaches that the composition can be for surgical implantation at a particular site (col. 61, lines 64-65).
The combination of applied references, however, do not expressly disclose that the collagen matrix composition is in the form of a collagen patch.
Serpooshan teaches an engineered acellular scaffold comprising type I collagen, endowed with specific physiomechanical properties improves cardiac function when used as a cardiac patch following myocardial infarction. Patches were grafted onto the infarcted myocardium in adult murine hearts immediately after ligation of the left anterior descending artery and the physiological outcomes were monitored by echocardiography and by hemodynamic and histological analyses four weeks post infarction. In comparison to infarcted hearts with no treatment, hearts bearing patches preserved contractility and significantly protected cardiac tissue from injury at the anatomical and functional levels. This improvement was accompanied by attenuated left ventricular remodeling, diminished fibrosis, and formation of a network of blood vessels within the infarct. Histological and immunostaining confirmed integration of the patch with native cardiac cells including fibroblasts, smooth muscle cells, epicardial cells, and immature cardiomyocytes. In summary, Serpooshan teaches an acellular biomaterial that promotes endogenous capacity of the infarcted myocardium to attenuate remodeling and improve heart function following myocardial infarction (abstract).
Serpooshan teaches that the goal of the study is to engineer a myocardial-friendly environment through the use of biocompatible, type I collagen gel with optimized physiomechanical properties in order to organize and condition the cardiac cells already present in the damaged heart tissue. Plastic compression technique was used to rapidly generate dense tissue scaffolds with optimal elastic modulus to support myocyte contractility (page 2, paragraph 5). Serpooshan further teaches that the collagen scaffolds were designed to achieve maximum myocyte contractility and the development of immature cardiomyocytes (page 6, paragraph 2).
Serpooshan also considers further investigations on therapeutic factors and/or cells that can be seeded within the engineered patch for cardiac repair following severe heart injuries (pages 6-7, conclusion).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the collagen matrix taught by the combination of Huang, US’484, Lutter, and US’898 with the collagen patch disclosed by Serpooshan for delivery of the reelin polypeptide treatment. An ordinarily skilled artisan would have been motivated to use the patch of Serpooshan as Serpooshan teaches that the collagen patch is able to promote the endogenous capacity of the infarcted myocardium, attenuate remodeling and improve heart function following heart injury, and provides support for myocyte contractility and development of immature cardiomyocytes, which would further contribute to the treatment methods disclosed by Huang, US’484, Lutter, and US’898. An ordinarily skilled artisan would have had a reasonable expectation of success because Huang, US’484, Lutter, and US’898 teach delivery of reelin via collagen matrix for the treatment of heart conditions, including myocardial infarction and ischemia, which is the same type of matrix and injury disclosed by Serpooshan. Additionally, Serpooshan also considered the seeding of the patches with therapeutic factors and/or cells.
Claims 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Serpooshan, V., et al (2013) The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function post myocardial infarction Biomaterials 34(36); 1-15 in view of US 9,486,484 B2 (Alfonso, Z. and J.K. Fraser) 8 Nov 2016, Lutter, S., et al (2012) Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation J. Cell. Biol. 197(6); 837-849, US 2003/0219898 A1 (Sugaya, K., et al) 27 Nov. 2003, and US 6,323,177 B1 (Curran, T. and G. D’Arcangelo) 27 Nov 2001.
The teachings of Serpooshan are as discussed above.
Serpooshan, however, does not disclose that the therapeutic factor seeded in the collagen patch is a reelin polypeptide or that the amount of reelin polypeptide in the patch is between 0.1 ng and 500 μg. Serpooshan also does not disclose that the reelin polypeptide comprises SEQ ID NO: 1.
The teachings of US’484, Lutter, and US’898 are as discussed above.
US’898 further teaches that reelin is a large extracellular matrix protein of approximately 400 kDa, which binds to the a3 subunit of integrin receptors expressed on neuronal cell surfaces, very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), triggering the adaptor function of the Dab-1 cytosolic protein. The clustering of integrin receptor subunits following reelin binding activates a tyrosine kinase to phosphorylate Dab-1 (page 16, [0158]).
Lutter also teaches that Reelin mediates its functions via two members of the low-density lipoprotein receptor family, VLDLR and ApoER2. Both receptors were expressed in cultured primary SMCs and LECs. In addition, VLDLR was expressed in lymphatic endothelia in vivo. This suggest that either cell type- LEC or SMC- could therefore respond to reelin to regulate SMC recruitment during collecting vessel formation (page 844, left column, paragraph 1).
US’177 teaches that the interaction between reelin and the very low density lipoprotein (VLDL) has been discovered. This allows for the development of a convenient assay system for receptor binding that is adaptable for screening modulators (agonists and antagonists) of the interaction between Reelin and the VLDL receptor or similar receptors (abstract).
US’177 teaches that the human reelin gene has been cloned and sequenced and the predicted protein encoded by the human gene is provided in SEQ ID NO: 1 (col. 18, lines 55-67). US’177, SEQ ID NO: 1 is identical to instant SEQ ID NO: 1.
US’177 teaches an assay of Reelin-VLDLR binding in which 20-100 ng of reelin was added to cells with and without the VLDL receptor. Western blot analysis was used to reveal the presence of reelin retained by the VLDL receptor (col. 29, lines 51-67). It is noted that 20-100 ng, as taught by US’177, is within the claimed range of 0.1 ng to 500 μg rendering the claimed range obvious per MPEP 2144.05 I.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the collagen patch of Serpooshan by seeding a reelin polypeptide in the collagen patch based on the teachings of US’484, Lutter, and US’898. It would have further been obvious to use the reelin polypeptide of SEQ ID NO: 1 and a reelin amount of 20-100 ng as disclosed by US’177.
An ordinarily skilled artisan would have been motivated to seed a reelin polypeptide in the collagen patch in order to promote expansion and tissue repair of the lymphatic system, which US’484 teaches is beneficial following cardiac events, such as myocardial infarction. The use of reelin is further supported by Lutter which demonstrates that reelin is important in regulating the formation of functional lymphatic vessels and is involved in a signaling pathway between LECs and SMCs. US’898 also motivates the inclusion of a reelin polypeptide teaching that reelin protein can be administered to heart related conditions to encourage migration of multipotent cells into the area of damage to start repair. An ordinarily skilled artisan would have had a reasonable expectation of success as Serpooshan teaches the use of collagen patches, which can be seeded with therapeutics, in the treatment and improvement of heart function following myocardial infarction, which is the same condition taught by both US’484 and US’898. Additionally, both US’484 and Lutter teach the importance of reelin in the formation of lymphatic vessels and both US’484 and US’898 teach methods of treating diseases or conditions of the heart using reelin. Additionally, US’484 teaches methods using a collagen matrix and Serpooshan teaches the seeding of therapeutics in such a matrix.
An ordinarily skilled artisan would have been motivated to use the reelin polypeptide disclosed by US’177 and 20-100 ng of reelin in the patch as US’177 teaches that the reelin polypeptide disclosed is that of human reelin and also demonstrates 20-100 ng of reelin for binding the VLDL receptor, which both US’898 and Lutter teach is one of the receptors that reelin signals through. Additionally, Lutter teaches that this receptor is present in SMCs and LECs and on lymphatic endothelia in vivo. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
It is also noted that the determination of the optimal amount of reelin is considered to be routine optimization where considerations for optimal amounts were known in the art. MPEP 2144.05 (II) A. states "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”. In this case, US’177 teaches the use of 20-100 ng of reelin for binding to the VLDL receptor that the references teach are present in SMCs, LECCs, and lymphatic endothelia in vivo. It would have been obvious to use these amounts as a starting point for routine optimization to determine the optimal amount of reelin for inclusion in the collagen patch to promote expansion and tissue repair of the lymphatic system following cardiac events.
Claims 13-14 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Huang, L.H., et al (2017) Cardiac Lymphatic vessels, transport, and healing of the infarcted heart JACC: Basic to translational science 2(4); 477-483 in view of US 9,486,484 B2 (Alfonso, Z. and J.K. Fraser) 8 Nov 2016, Lutter, S., et al (2012) Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation J. Cell. Biol. 197(6); 837-849 and US 2003/0219898 A1 (Sugaya, K., et al) 27 Nov. 2003 as applied to claim 1 above, and in further view of Serpooshan, V., et al (2013) The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function post myocardial infarction Biomaterials 34(36); 1-15 and US 6,323,177 B1 (Curran, T. and G. D’Arcangelo) 27 Nov 2001.
The combination of Huang, US’484, Lutter, and US’898 are as discussed in detail above.
The combination of applied references, however, do not disclose that the reelin comprises SEQ ID NO: 1 as recited in claim 13, that the reelin is included in a collagen patch as recited in claim 14, or that the reelin polypeptide is administered in an amount between 1 ng and 500 μg as recited in claim 21.
The teachings of Serpooshan and US’177 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the collagen matrix taught by the combination of Huang, US’484, Lutter, and US’898 with the collagen patch disclosed by Serpooshan for delivery of the reelin polypeptide treatment. It would have further been obvious to use the reelin polypeptide of SEQ ID NO: 1 and a reelin amount of 20-100 ng as disclosed by US’177.
An ordinarily skilled artisan would have been motivated to use the patch of Serpooshan as Serpooshan teaches that the collagen patch is able to promote the endogenous capacity of the infarcted myocardium, attenuate remodeling and improve heart function following heart injury, and provides support for myocyte contractility and development of immature cardiomyocytes, which would further contribute to the treatment methods disclosed by Huang, US’484, Lutter, and US’898. An ordinarily skilled artisan would have had a reasonable expectation of success because Huang, US’484, Lutter, and US’898 teach delivery of reelin via collagen matrix for the treatment of heart conditions, including myocardial infarction and ischemia, which is the same type of matrix and injury disclosed by Serpooshan. Additionally, Serpooshan also considered the seeding of the patches with therapeutic factors and/or cells.
An ordinarily skilled artisan would have been motivated to use the reelin polypeptide disclosed by US’177 and 20-100 ng of reelin in the patch as US’177 teaches that the reelin polypeptide disclosed is that of human reelin and also demonstrates 20-100 ng of reelin for binding the VLDL receptor, which both US’898 and Lutter teach is one of the receptors that reelin signals through. Additionally, Lutter teaches that this receptor is present in SMCs and LECs and on lymphatic endothelia in vivo. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
It is also noted that the determination of the optimal amount of reelin is considered to be routine optimization where considerations for optimal amounts were known in the art. See MPEP 2144.05 (II) A. In this case, US’177 teaches the use of 20-100 ng of reelin for binding to the VLDL receptor that the references teach are present in SMCs, LECCs, and lymphatic endothelia in vivo. It would have been obvious to use these amounts as a starting point for routine optimization to determine the optimal amount of reelin for inclusion in the collagen patch to promote expansion and tissue repair of the lymphatic system following cardiac events.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Huang, L.H., et al (2017) Cardiac Lymphatic vessels, transport, and healing of the infarcted heart JACC: Basic to translational science 2(4); 477-483 in view of US 9,486,484 B2 (Alfonso, Z. and J.K. Fraser) 8 Nov 2016, Lutter, S., et al (2012) Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation J. Cell. Biol. 197(6); 837-849 and US 2003/0219898 A1 (Sugaya, K., et al) 27 Nov. 2003 as applied to claim 1 above, and in further view of Lam, N.T. and H.A. Sadek (2018) Neonatal Heart Regeneration, Comprehensive literature review Circulation 412-423.
The combination of Huang, US’484, Lutter, and US’898 teach the method of claim 1 as discussed in detail above.
As discussed in detail above, the combination of applied references teaches that the use of lymphatic vasculature directed therapies, including reelin polypeptides, can improve cardiac regeneration in a subject (see, for instance, US’484, lines 23-42; US’898, [0029]).
The combination of applied references; however, does not teach that the subject is neonatal.
Lam teaches that the neonatal mammalian heart is capable of regeneration after various types of injury. Since the first report in 2011, a number of groups have reported their findings on neonatal heart regeneration. Lam provides a review with a comprehensive analysis of heart regeneration studies in neonatal mammals conducted to date (abstract, background). Lam teaches that both apical resection and ischemic infarction injury in neonatal mice results in a robust regenerative response, mediated by cardiomyocyte proliferation (abstract, results).
Lam teaches that, in models of embryonic zebrafish, hearts were amputated to induce a regenerative response. Studies demonstrated that cardiac regeneration in zebrafish is primarily mediated by proliferation of preexisting cardiomyocytes. Not unlike zebrafish cardiomyocytes, mammalian neonatal cardiomyocytes have been known to retain mitotic capacity during the first few days of life, and have been used extensively to study cardiomyocyte cell cycle kinetics in vitro (page 413, left column, paragraph 1). Based on these characteristics of neonatal cardiomyocytes, Lam studied the regenerative capacity of the neonatal heart using a similar model and found robust regenerative responses characterized by marked induction of cardiomyocyte proliferation with replacement of the lost myocardium 21 days postresection. This remarkable regenerative response was mediated by proliferation of preexisting cardiomyocytes (page 413, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the method disclosed by the combination of Huang, US’484, Lutter, and US’898 in a neonatal subject based on the teachings of Lam with a reasonable expectation that the method would improve cardiac regeneration. One of ordinary skill in the art would have been motivated to treat a neonatal subject as Lam teaches that the neonatal mammalian heart is capable of regeneration after injury that is mediated by cardiomyocyte proliferation and Huang teaches that myocardial ischemia can cause death of cardiac myocytes, but that heart conditions such as ischemia and infarction may be treated by targeting the lymphatic vasculature. Huang also demonstrates that using a therapeutic that targets the lymphatic vasculature improved the rate and quality of cardiac healing in mice and rat models. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Response to Arguments
Applicant’s arguments in the response filed 05/12/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant argues that the claims have been amended to recite that the method is for reducing cardiomyocyte death. Applicant argues that, as disclosed, the reduction of cardiomyocyte apoptosis by administration of reelin correlates with improved heart function and reduction in fibrotic tissue after myocardial infarction. Applicant argues that these benefits were not disclosed by the combination of applied references.
These arguments are not persuasive.
In the rejections of the instant office action, the reference Huang has been applied in order to demonstrate that the death of cardiac myocytes had been linked to myocardial ischemia and to further demonstrate that therapeutics targeting the lymphatic vasculature had been considered following myocardial ischemia and infarction.
Additionally, as discussed in detail in the rejections of the instant office action, while one of ordinary skill in the art would reasonably expect that by treating ischemia, the death of cardiac myocytes would be reduced, the function of reducing cardiac myocytes would also flow naturally from following the suggestions of the prior art. That is to say that, by treating ischemia with a therapeutic targeting the lymphatic vasculature, such as reelin, the death of cardiac myocytes would naturally, and mechanistically, be reduced. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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