Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Detailed Action
This action is in response to the papers filed March 23, 2026.
Amendments
Applicant's response and amendments, filed March 23, 2026, to the prior Office Action is acknowledged. Applicant has cancelled Claims 2-5 and 8-14, and amended Claim 1.
Claims 1, 6-7, and 15-16 are pending and under examination.
Priority
This application is a continuation of application 15/788,438 filed on October 19, 2017, now abandoned, which is a continuation of application 12/309,158 filed on December 24, 2009, now abandoned, which is a 371 of PCT/AU2007/000974 filed on July 12, 2007. Applicant’s claim for the benefit of a prior-filed application provisional application 60/830,651 filed on July 12, 2006 and 60/830,649 filed on July 12, 2006 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Priority
This application is a continuation of application 15/788,438 filed on October 19, 2017, now abandoned,
which is a continuation of application 12/309,158 filed on December 24, 2009, now abandoned,
which is a 371 of PCT/AU2007/000974 filed on July 12, 2007.
Applicant’s claim for the benefit of a prior-filed application provisional application 60/830,651 filed on July 12, 2006 and 60/830,649 filed on July 12, 2006 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Claim Rejections - 35 USC § 112
1. The prior rejections of Claims 1, 6-7, and 15-16 a under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in light of Applicant’s amendment to independent Claim 1 to recite:
i) intravitreal injection; and
ii) a cell population comprising at least 1x10^5 cells, at least 5% of which are STRO-1+, TNAP+ MPCs (syn. a cell population comprising at least 1x10^5 cells, at least 5000 of which are STRO-1+, TNAP+ MPCs),
which the Examiner finds persuasive.
The phrase “so as to reduce or eliminate at least one symptom of macular degeneration or diabetic retinopathy, whichever is applicable” is not considered to further limit the claimed method because it is considered axiomatic, per natural law of cell biology and the logic of the claim, that the intravitreal administration of a cell population comprising at least 1x10^5 cells, at least 5000 of which are STRO-1+, TNAP+ MPCs, will inherently and necessarily reduce or eliminate, by however minor amount, at least one symptom of macular degeneration or diabetic retinopathy.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
2. Claims 1, 7, and 15-16 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Caplan et al (WO 04/084950; of record in IDS) in view of Gronthos et al (WO 06/108229; filed April 12, 2006; priority to April 12, 2005; of record), Snable et al (WO 98/34485; of record), and Otani et al (2002; of record in IDS).
Determining the scope and contents of the prior art.
With respect to Claim 1, Caplan et al disclosed a method of treating or preventing an angiogenesis-related disease in a subject, whereby said disease is an ocular angiogenesis disease, more specifically macular degeneration (pg 4, line 13; pg 5, lines 29-30), the method comprising the step of administering a mesenchymal precursor cell (pg 2, lines 17-24, e.g. totipotent stem cell, pluripotent stem cell, mesenchymal stem cell, or multipotent stem cell) that is STRO-1+, CD146+ (pg 3, lines 8-11).
Caplan et al disclosed the progenitor cell composition is administered to the target diseased/injured site (pg 4, line 31-pg 5, line 1, “the progenitor cells may be delivered to a subject…by injection into the target tissue”; pg 2, line 7, “delivering a progenitor cell to a target tissue in a subject”; pg 4, lines 11-13, “target tissue is…retinal tissue”) so that the malfunctioning target tissue, e.g. macular degeneration (pg 5, lines 29-30; pg 34, line 9), can be replaced with functioning tissue derived from the progenitor cell composition (syn. “a therapeutically effective amount”) (pg 34, lines 1-3).
Caplan et al disclosed wherein the subject is human (e.g. pg 22, line 26).
Caplan et al do not disclose the multipotent cell population comprising STRO-1+, CD146+ mesenchymal precursor cells also express TNAP. However, prior to the instantly claimed invention, Gronthos et al (‘229) is considered relevant prior art for having disclosed human mesenchymal precursor cells (e.g. pg 1, line 24) that express a high level of STRO-1 obtained from human bone marrow (e.g. pg 15, lines 5-16), whereby said MPCs can differentiate into retinal tissue types (e.g. pg 21, line 28).
Gronthos et al (‘229) disclosed that TNAP is a marker that can be used for the isolation and enrichment of immature multipotent cells from a variety of tissue sources, and is not present on CD34+ hematopoietic stem cells in bone marrow aspirates (pg 3, lines 17-32).
Gronthos et al (‘229) disclosed that enrichment for adult multipotent cells may further include selection for Stro-1 and CD146 expression (pg 6, lines 5-10; pg 21, lines 15-17).
Gronthos et al (‘229) disclosed the enriched multipotent cell population comprises between 5%, 10%, or up to 95% TNAP+ cells (pg 8, lines 10-12), within which about 12% to 45% of the cells are also Stro-1+ (pg 20, lines 1-3; pg 21, lines 8-9, “more preferably at least 45% of the cells are STRO-1+”).
Gronthos et al (‘229) disclosed enriching a bone marrow cell composition for expression of both TNAP and Stro-1 (e.g. pg 60, Example 5, Table 2; yielding a 410-fold enrichment over unfractionated BMMNCs).
Gronthos et al (‘229) disclosed the cultures initially selected for TNAP+ upregulated Stro-1, presumably reflecting proliferation without spontaneous differentiation (pgs 61-62, joining ¶).
Gronthos et al (‘229) disclosed wherein a population of about 1x10^5 cultured colony-forming unit cells naturally comprises about 4700 STRO-1(bright), TNAP+ MPCs (syn. 4.7%; e.g. pg 60, table).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Instant specification fails to disclose an element of criticality for “at least 5%”, as opposed to ‘at least 4.7%’ disclosed by Gronthos et al (‘229).
Gronthos et al (‘229) disclosed the administration of an enriched population of 5x10^6 STRO-1(bright) stem cells (e.g. pg 74, line 29), which comprises at least 84% STRO-1(bright) cells and TNAP+ cells (e.g. pg 61, lines 26-35).
Thus, the ordinary artisan would have reasonably inferred the administered cell composition comprising at least 5x10^6 cells enriched MPCs comprises at least 4.2x10^6 STRO-1+, TNAP+ cells.
While Caplan et al disclosed macular degeneration as a disease/injury to be treated (e.g. pg 5, lines 29-30; pg 34, line 9), and those of ordinary skill in the art would have immediately recognize that such requires administration of the cells to the eye (pg 2, line 7, “delivering a progenitor cell to a target tissue in a subject”; pg 4, lines 11-13, “target tissue is…retinal tissue”; pg 4, line 31-pg 5, line 1, “the progenitor cells may be delivered to a subject…by injection into the target tissue”), Caplan et al do not disclose a working example in which the progenitor/stem cells are administered to the eye for the treatment of the ocular disease.
Neither Caplan et al nor Gronthos et al (‘229) disclose intravitreal administration.
However, prior to the instantly claimed invention, Snable et al considered relevant prior art for having disclosed a method of treating an ocular disorder in a subject comprising the step of transplanting a therapeutically effective amount of pluripotent stem cells into the eye, wherein the ocular disorder is age-related macular degeneration (Abstract), recognized in the art to be the predominant form of macular degeneration (pg 2, lines 24-26). Snable et al disclosed the intravitreal administration (pgs 8-9, joining para, “vitreous-retina interface”) of 3x10^4 cells of an essentially pure therapeutic cell population (pg 8, line 28) at a concentration of 3x10^7 cells/ml (pg 9, lines 24-30; 1 microliter volume injected = 3x10^4 cells) in a rat animal model system. Snable et al also disclosed the administration of 4x10^4 cells, 8x10^4 cells, and 1.2x10^5 cells (Example 3, pg 15, lines 2-3).
Snable et al disclosed wherein the subject may be human (e.g. pg 1, line 4; pg 8, line 15; pg 8, lines 29-30, “for human use”).
Similarly, Otani et al is considered relevant prior art for having taught that bone marrow-derived hematopoietic stem cells and endothelial precursor cells are useful for modulating abnormal blood vessel growth in age-related macular degeneration (ARMD) and other retinal degenerations associated with abnormal vasculature (pg 1004, col. 2). The BM-HSCs stably incorporate into developing retinal vasculature, preventing abnormalities of the vessels such as hemorrhage or edema, and this effect might, in fact, alleviate the hypoxia that originally stimulated the neovascularization (pg 1006, col. 1; pg 1008, col. 2). Otani et al taught the intravitreal administration of 1x10^5 bone marrow-derived stem cells into the eye of a mouse animal model system (pg 1005, col. 2).
Ascertaining the differences between the prior art and the claims at issue, and Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in medicine and cell biology. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to use human cell composition comprising at least 5% STRO-1+, TNAP+ mesenchymal precursor cells in a method of treating an ocular angiogenesis disease caused by excessive neovascularization, e.g. macular degeneration, so as to reduce at least one symptom of macular degeneration, e.g. such excessive neovascularization. in a human subject’s eye, the method comprising the step of intravitreal administration of at least 1x10^5 cells comprising said at least 5% STRO-1+, TNAP+ MPCs with a reasonable expectation of success because:
i) the ordinary artisan previously recognized the scientific and technical concepts of using CD146+, STRO-l+ mesenchymal precursor cells to treat an ocular angiogenesis disease caused by excessive neovascularization in the eye of a subject, including human subjects, to wit, macular degeneration (Caplan et al);
ii) the ordinary artisan previously recognized the scientific concepts that TNAP+-selected mesenchymal precursor cells naturally express CD146 and STRO-1 during expansion in culture, whereby the cultures initially selected for TNAP+ upregulated STRO-1, presumably reflecting proliferation without spontaneous differentiation (Gronthos et al, pgs 61-62, joining ¶); and
iii) the ordinary artisan previously recognized the scientific concepts that the bone marrow-derived mesenchymal precursor cells are capable of differentiating into vascular endothelial cells and pericytes (Gronthos et al, pg 21, lines 30-32), whereby bone marrow-derived hematopoietic stem cells and endothelial precursor cells are useful for modulating abnormal blood vessel growth in age-related macular degeneration (ARMD) and other retinal degenerations associated with abnormal vasculature, whereby the stem cells stably incorporate into developing retinal vasculature, preventing abnormalities of the vessels such as hemorrhage or edema, and this effect might, in fact, alleviate the hypoxia that originally stimulated the neovascularization (Otani et al).
Gronthos et al (‘229) disclosed wherein a population of about 1x10^5 cultured colony-forming unit cells naturally comprises about 4700 STRO-1(bright), TNAP+ MPCs (syn. 4.7%; e.g. pg 60, table).
Gronthos et al (‘229) disclosed the administration of an enriched population of 5x10^6 STRO-1(bright) stem cells (e.g. pg 74, line 29), which comprises at least 84% STRO-1(bright) cells and TNAP+ cells (e.g. pg 61, lines 26-35).
Thus, the ordinary artisan would have reasonably inferred the administered cell composition comprising at least 5x10^6 cells enriched MPCs comprises at least 4.2x10^6 STRO-1+, TNAP+ cells.
Snable et al disclosed the intravitreal administration (pgs 8-9, joining para, “vitreous-retina interface”) of 3x10^4 cells of an essentially pure therapeutic cell population (pg 8, line 28) at a concentration of 3x10^7 cells/ml (pg 9, lines 24-30; 1 microliter volume injected = 3x10^4 cells) in a rat animal model system. Snable et al also disclosed the administration of 4x10^4 cells, 8x10^4 cells, and 1.2x10^5 cells (Example 3, pg 15, lines 2-3).
Otani et al taught the intravitreal administration of 1x10^5 bone marrow-derived stem cells into the eye of a mouse animal model system (pg 1005, col. 2).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 7, the limitation ‘wherein the stem cells are obtained from bone marrow’ (Claim 7) is considered a product-by-process limitations that are not viewed as positively limiting the claimed product [human cell population comprising STRO-1+, TNAP+ MPC] absent a showing that the process of making recited in Claim 7 imparts a novel or unexpected property to the claimed product, as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the human cell population comprising STRO-1+, TNAP+ MPCs were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
Nevertheless, Gronthos et al (‘229) disclosed wherein the human mesenchymal precursor cells that express a high level of STRO-1 obtained from human bone marrow (e.g. pg 15, lines 5-16).
With respect to Claim 15, Gronthos et al (‘229) disclosed wherein the human mesenchymal precursor cells may be expanded via in vitro culture prior to administration to the subject (e.g. pg 11, line 21; pg 15, lines 18-29, “culture expanded multipotential cells”; pg 76, lines 29-30, “culture-expanded TNAP enriched cells”).
With respect to Claim 16, Gronthos et al (‘229) disclosed wherein the MPCs may be genetically modified by the introduction of exogenous nucleic acids for gene therapy (e.g. pg 11, lines 6-10; pg 30, line 14).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Caplan et al do not disclose each and every element of the amended Claim 1.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant claim(s) is/are not rejected under pre-AIA 35 U.S.C. 102 (anticipation), but rather pre-AIA 35 U.S.C. 103 (obviousness).
Applicant argues that Caplan et al do not disclose a cell population enriched for STRo-1+ TNAP+ MPCs, i.e. a cell population 5% of which are STRo-1+ TNAP+ multipotential MPCs
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Gronthos et al (‘229) disclosed wherein a population of about 1x10^5 cultured colony-forming unit cells naturally comprises about 4700 STRO-1(bright), TNAP+ MPCs (syn. 4.7%; e.g. pg 60, table).
Gronthos et al (‘229) disclosed the administration of an enriched population of 5x10^6 STRO-1(bright) stem cells (e.g. pg 74, line 29), which comprises at least 84% STRO-1(bright) cells and TNAP+ cells (e.g. pg 61, lines 26-35).
Thus, the ordinary artisan would have reasonably inferred the administered cell composition comprising at least 5x10^6 cells enriched MPCs comprises at least 4.2x10^6 STRO-1+, TNAP+ cells.
Snable et al disclosed the intravitreal administration (pgs 8-9, joining para, “vitreous-retina interface”) of 3x10^4 cells of an essentially pure therapeutic cell population (pg 8, line 28) at a concentration of 3x10^7 cells/ml (pg 9, lines 24-30; 1 microliter volume injected = 3x10^4 cells) in a rat animal model system. Snable et al also disclosed the administration of 4x10^4 cells, 8x10^4 cells, and 1.2x10^5 cells (Example 3, pg 15, lines 2-3).
Otani et al taught the intravitreal administration of 1x10^5 bone marrow-derived stem cells into the eye of a mouse animal model system (pg 1005, col. 2).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Applicant argues that Gronthos et al discloses treatment of bone conditions.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Caplan et al disclosed a method of treating or preventing an angiogenesis-related disease in a subject, whereby said disease is an ocular angiogenesis disease, more specifically macular degeneration (pg 4, line 13; pg 5, lines 29-30), the method comprising the step of administering a mesenchymal precursor cell (pg 2, lines 17-24, e.g. totipotent stem cell, pluripotent stem cell, mesenchymal stem cell, or multipotent stem cell) that is STRO-1+, CD146+ (pg 3, lines 8-11).
Caplan et al disclosed the progenitor cell composition is administered to the target diseased/injured site (pg 4, line 31-pg 5, line 1, “the progenitor cells may be delivered to a subject…by injection into the target tissue”; pg 2, line 7, “delivering a progenitor cell to a target tissue in a subject”; pg 4, lines 11-13, “target tissue is…retinal tissue”) so that the malfunctioning target tissue, e.g. macular degeneration (pg 5, lines 29-30; pg 34, line 9), can be replaced with functioning tissue derived from the progenitor cell composition (syn. “a therapeutically effective amount”) (pg 34, lines 1-3).
Gronthos et al (‘229) disclosed the administration of an enriched population of 5x10^6 STRO-1(bright) stem cells (e.g. pg 74, line 29), which comprises at least 84% STRO-1(bright) cells and TNAP+ cells (e.g. pg 61, lines 26-35).
Snable et al disclosed a method of treating an ocular disorder in a subject comprising the step of transplanting a therapeutically effective amount of pluripotent stem cells into the eye, wherein the ocular disorder is age-related macular degeneration (Abstract), recognized in the art to be the predominant form of macular degeneration (pg 2, lines 24-26). Snable et al disclosed the intravitreal administration (pgs 8-9, joining para, “vitreous-retina interface”) of 3x10^4 cells of an essentially pure therapeutic cell population (pg 8, line 28) at a concentration of 3x10^7 cells/ml (pg 9, lines 24-30; 1 microliter volume injected = 3x10^4 cells) in a rat animal model system. Snable et al also disclosed the administration of 4x10^4 cells, 8x10^4 cells, and 1.2x10^5 cells (Example 3, pg 15, lines 2-3).
Otani et al taught that bone marrow-derived hematopoietic stem cells and endothelial precursor cells are useful for modulating abnormal blood vessel growth in age-related macular degeneration (ARMD) and other retinal degenerations associated with abnormal vasculature (pg 1004, col. 2). The BM-HSCs stably incorporate into developing retinal vasculature, preventing abnormalities of the vessels such as hemorrhage or edema, and this effect might, in fact, alleviate the hypoxia that originally stimulated the neovascularization (pg 1006, col. 1; pg 1008, col. 2). Otani et al taught the intravitreal administration of 1x10^5 bone marrow-derived stem cells into the eye of a mouse animal model system (pg 1005, col. 2).
Applicant argues that neither Caplan et al nor Gronthos et al suggest that STRO-1+, TNAP+ MPCs could be used to treat macular degeneration.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Caplan et al disclosed a method of treating or preventing an angiogenesis-related disease in a subject, whereby said disease is an ocular angiogenesis disease, more specifically macular degeneration (pg 4, line 13; pg 5, lines 29-30), the method comprising the step of administering a mesenchymal precursor cell (pg 2, lines 17-24, e.g. totipotent stem cell, pluripotent stem cell, mesenchymal stem cell, or multipotent stem cell) that is STRO-1+, CD146+ (pg 3, lines 8-11).
Caplan et al disclosed the progenitor cell composition is administered to the target diseased/injured site (pg 4, line 31-pg 5, line 1, “the progenitor cells may be delivered to a subject…by injection into the target tissue”; pg 2, line 7, “delivering a progenitor cell to a target tissue in a subject”; pg 4, lines 11-13, “target tissue is…retinal tissue”) so that the malfunctioning target tissue, e.g. macular degeneration (pg 5, lines 29-30; pg 34, line 9), can be replaced with functioning tissue derived from the progenitor cell composition (syn. “a therapeutically effective amount”) (pg 34, lines 1-3).
Gronthos et al (‘229) disclosed the administration of an enriched population of 5x10^6 STRO-1(bright) stem cells (e.g. pg 74, line 29), which comprises at least 84% STRO-1(bright) cells and TNAP+ cells (e.g. pg 61, lines 26-35).
Applicant argues that Snable is directed to hNT-neurons, not STRO-1+, TNAP+ MPCs.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Caplan et al disclosed a method of treating or preventing an angiogenesis-related disease in a subject, whereby said disease is an ocular angiogenesis disease, more specifically macular degeneration (pg 4, line 13; pg 5, lines 29-30), the method comprising the step of administering a mesenchymal precursor cell (pg 2, lines 17-24, e.g. totipotent stem cell, pluripotent stem cell, mesenchymal stem cell, or multipotent stem cell) that is STRO-1+, CD146+ (pg 3, lines 8-11).
Caplan et al disclosed the progenitor cell composition is administered to the target diseased/injured site (pg 4, line 31-pg 5, line 1, “the progenitor cells may be delivered to a subject…by injection into the target tissue”; pg 2, line 7, “delivering a progenitor cell to a target tissue in a subject”; pg 4, lines 11-13, “target tissue is…retinal tissue”) so that the malfunctioning target tissue, e.g. macular degeneration (pg 5, lines 29-30; pg 34, line 9), can be replaced with functioning tissue derived from the progenitor cell composition (syn. “a therapeutically effective amount”) (pg 34, lines 1-3).
Gronthos et al (‘229) disclosed the administration of an enriched population of 5x10^6 STRO-1(bright) stem cells (e.g. pg 74, line 29), which comprises at least 84% STRO-1(bright) cells and TNAP+ cells (e.g. pg 61, lines 26-35).
Snable et al disclosed a method of treating an ocular disorder in a subject comprising the step of transplanting a therapeutically effective amount of pluripotent stem cells into the eye, wherein the ocular disorder is age-related macular degeneration (Abstract), recognized in the art to be the predominant form of macular degeneration (pg 2, lines 24-26). Snable et al disclosed the intravitreal administration (pgs 8-9, joining para, “vitreous-retina interface”) of 3x10^4 cells of an essentially pure therapeutic cell population (pg 8, line 28) at a concentration of 3x10^7 cells/ml (pg 9, lines 24-30; 1 microliter volume injected = 3x10^4 cells) in a rat animal model system. Snable et al also disclosed the administration of 4x10^4 cells, 8x10^4 cells, and 1.2x10^5 cells (Example 3, pg 15, lines 2-3).
Otani et al taught that bone marrow-derived hematopoietic stem cells and endothelial precursor cells are useful for modulating abnormal blood vessel growth in age-related macular degeneration (ARMD) and other retinal degenerations associated with abnormal vasculature (pg 1004, col. 2). The BM-HSCs stably incorporate into developing retinal vasculature, preventing abnormalities of the vessels such as hemorrhage or edema, and this effect might, in fact, alleviate the hypoxia that originally stimulated the neovascularization (pg 1006, col. 1; pg 1008, col. 2). Otani et al taught the intravitreal administration of 1x10^5 bone marrow-derived stem cells into the eye of a mouse animal model system (pg 1005, col. 2).
Applicant argues that Otani et al is directed to Lin-HSCs, not STRO-1+, TNAP+ MPCs.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Caplan et al disclosed a method of treating or preventing an angiogenesis-related disease in a subject, whereby said disease is an ocular angiogenesis disease, more specifically macular degeneration (pg 4, line 13; pg 5, lines 29-30), the method comprising the step of administering a mesenchymal precursor cell (pg 2, lines 17-24, e.g. totipotent stem cell, pluripotent stem cell, mesenchymal stem cell, or multipotent stem cell) that is STRO-1+, CD146+ (pg 3, lines 8-11).
Caplan et al disclosed the progenitor cell composition is administered to the target diseased/injured site (pg 4, line 31-pg 5, line 1, “the progenitor cells may be delivered to a subject…by injection into the target tissue”; pg 2, line 7, “delivering a progenitor cell to a target tissue in a subject”; pg 4, lines 11-13, “target tissue is…retinal tissue”) so that the malfunctioning target tissue, e.g. macular degeneration (pg 5, lines 29-30; pg 34, line 9), can be replaced with functioning tissue derived from the progenitor cell composition (syn. “a therapeutically effective amount”) (pg 34, lines 1-3).
Gronthos et al (‘229) disclosed the administration of an enriched population of 5x10^6 STRO-1(bright) stem cells (e.g. pg 74, line 29), which comprises at least 84% STRO-1(bright) cells and TNAP+ cells (e.g. pg 61, lines 26-35).
Snable et al disclosed a method of treating an ocular disorder in a subject comprising the step of transplanting a therapeutically effective amount of pluripotent stem cells into the eye, wherein the ocular disorder is age-related macular degeneration (Abstract), recognized in the art to be the predominant form of macular degeneration (pg 2, lines 24-26). Snable et al disclosed the intravitreal administration (pgs 8-9, joining para, “vitreous-retina interface”) of 3x10^4 cells of an essentially pure therapeutic cell population (pg 8, line 28) at a concentration of 3x10^7 cells/ml (pg 9, lines 24-30; 1 microliter volume injected = 3x10^4 cells) in a rat animal model system. Snable et al also disclosed the administration of 4x10^4 cells, 8x10^4 cells, and 1.2x10^5 cells (Example 3, pg 15, lines 2-3).
Otani et al taught that bone marrow-derived hematopoietic stem cells and endothelial precursor cells are useful for modulating abnormal blood vessel growth in age-related macular degeneration (ARMD) and other retinal degenerations associated with abnormal vasculature (pg 1004, col. 2). The BM-HSCs stably incorporate into developing retinal vasculature, preventing abnormalities of the vessels such as hemorrhage or edema, and this effect might, in fact, alleviate the hypoxia that originally stimulated the neovascularization (pg 1006, col. 1; pg 1008, col. 2). Otani et al taught the intravitreal administration of 1x10^5 bone marrow-derived stem cells into the eye of a mouse animal model system (pg 1005, col. 2).
3. Claim 6 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Caplan et al (WO 04/084950; of record in IDS) in view of Gronthos et al (WO 06/108229; filed April 12, 2006; priority to April 12, 2005; of record), Snable et al (WO 98/34485; of record), and Otani et al (2002; of record in IDS), as applied to Claims 1, 7, and 15-16 above, and in further view of Hamdi et al (2003; abstract only; of record).
Determining the scope and contents of the prior art.
Snable et al disclosed a method of treating an ocular disorder in a subject comprising the step of transplanting a therapeutically effective amount of pluripotent stem cells into the eye, wherein the ocular disorder is age-related macular degeneration (Abstract).
Neither Caplan et al, Gronthos et al, Snable et al, nor Otani et al teach/disclose wherein the macular degeneration is a dry age-related macular degeneration or wet age-related macular degeneration.
However, prior to the instantly claimed invention, and with respect to Claim 6, those of ordinary skill in the art immediately recognized that age-related macular degeneration comes in two forms: wet and dry (Hamdi et al). Thus, absent evidence to the contrary, the ordinary artisan would have understood that Snable discloses dry- and wet- age-related macular degeneration.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute macular degeneration as disclosed by Caplan et al for age-related macular degeneration, more specifically the wet or dry form of age-related macular degeneration, as disclosed by Snable in a stem cell therapy method with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” An artisan would be motivated to substitute macular degeneration for the wet or dry form of age-related macular degeneration in a stem cell therapy method because Snable disclosed that age-related macular degeneration is the predominant form of macular degeneration, affecting six million people in the United States alone, and those of ordinary skill in the art immediately recognized that age-related macular degeneration comes in two forms: wet and dry.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Hamdi et al do not cure the defect(s) of Caplan et al, Gronthos et al, and Snable et al.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner’s response to Applicant's argument(s) regarding Caplan et al, Gronthos et al, and Snable et al are discussed above and incorporated herein. Applicant does not contest the teachings of Snable et al and Hamdi et al as applied to the obviousness to substitute macular degeneration as disclosed by Caplan et al for age-related macular degeneration, more specifically the wet or dry form of age-related macular degeneration, as disclosed by Snable in a stem cell therapy method with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” An artisan would be motivated to substitute macular degeneration for the wet or dry form of age-related macular degeneration in a stem cell therapy method because Snable disclosed that age-related macular degeneration is the predominant form of macular degeneration, affecting six million people in the United States alone, and those of ordinary skill in the art immediately recognized that age-related macular degeneration comes in two forms: wet and dry.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
4. Claims 1, 7, and 15-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 12, and 14 of U.S. Patent No. 8,894,972 in view of Gronthos et al (WO 06/108229; filed April 12, 2006; priority to April 12, 2005; of record), Snable et al (WO 98/34485; of record), and Otani et al (2002; of record in IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other.
‘972 claims (claim 1) a method of treating diabetes mellitus, e.g. Type I or Type II diabetes mellitus (claim 14), the method comprising the step of administering STRO-1+ cells to the subject, wherein the STRO-1+ cells are STRO-1bright and TNAP+ (claim 9).
The ‘972 specification discloses the written description of the STRO-1+ cells are MPCs (e.g. col. 5, lines 14-15) obtained from bone marrow (e.g. col. 15, line 64).
The ‘972 specification discloses diabetes mellitis abnormalities include retinal complications (e.g. col. 2, lines 15-16), whereby the therapeutic result includes reducing the severity of one or more complications of retinopathy or cataracts (e.g. col. 15, lines 14-20).
The instant specification discloses an embodiment of the angiogenesis-related disorder includes Type I or Type II diabetes (e.g. pg 2, line 27).
Gronthos et al (‘229) is considered relevant prior art for having disclosed human mesenchymal precursor cells (e.g. pg 1, line 24) that express a high level of STRO-1 obtained from human bone marrow (e.g. pg 15, lines 5-16), whereby said MPCs can differentiate into retinal tissue types (e.g. pg 21, line 28).
Gronthos et al (‘229) disclosed that TNAP is a marker that can be used for the isolation and enrichment of immature multipotent cells from a variety of tissue sources, and is not present on CD34+ hematopoietic stem cells in bone marrow aspirates (pg 3, lines 17-32).
Gronthos et al (‘229) disclosed that enrichment for adult multipotent cells may further include selection for Stro-1 and CD146 expression (pg 6, lines 5-10; pg 21, lines 15-17).
Gronthos et al (‘229) disclosed the enriched multipotent cell population comprises between 5%, 10%, or up to 95% TNAP+ cells (pg 8, lines 10-12), within which about 12% to 45% of the cells are also Stro-1+ (pg 20, lines 1-3; pg 21, lines 8-9).
Gronthos et al (‘229) disclosed enriching a bone marrow cell composition for expression of both TNAP and Stro-1 (e.g. pg 60, Example 5, Table 2; yielding a 410-fold enrichment over unfractionated BMMNCs).
Gronthos et al (‘229) disclosed the cultures initially selected for TNAP+ upregulated Stro-1, presumably reflecting proliferation without spontaneous differentiation (pgs 61-62, joining ¶).
Snable et al considered relevant prior art for having disclosed a method of treating an ocular disorder in a subject comprising the step of transplanting a therapeutically effective amount of pluripotent stem cells into the eye, wherein the ocular disorder is age-related macular degeneration (Abstract), recognized in the art to be the predominant form of macular degeneration (pg 2, lines 24-26). Snable et al disclosed the intravitreal administration (pgs 8-9, joining para, “vitreous-retina interface”) of 3x10^4 cells of an essentially pure therapeutic cell population (pg 8, line 28) at a concentration of 3x10^7 cells/ml (pg 9, lines 24-30; 1 microliter volume injected = 3x10^4 cells) in a rat animal model system. Snable et al also disclosed the administration of 4x10^4 cells, 8x10^4 cells, and 1.2x10^5 cells (Example 3, pg 15, lines 2-3).
Snable et al disclosed wherein the subject may be human (e.g. pg 1, line 4; pg 8, line 15; pg 8, lines 29-30, “for human use”).
Similarly, Otani et al is considered relevant prior art for having taught that age-related macular degeneration and diabetic retinopathy are the leading causes of vision loss in industrialized nations (e.g. pg 1004, col. 1, Introduction). Bone marrow-derived hematopoietic stem cells and endothelial precursor cells are useful for modulating abnormal blood vessel growth in age-related macular degeneration (ARMD) and other retinal degenerations associated with abnormal vasculature (pg 1004, col. 2).
The BM-HSCs stably incorporate into developing retinal vasculature, preventing abnormalities of the vessels such as hemorrhage or edema, and this effect might, in fact, alleviate the hypoxia that originally stimulated the neovascularization (pg 1006, col. 1; pg 1008, col. 2). Otani et al taught the intravitreal administration of 1x10^5 bone marrow-derived stem cells into the eye of a mouse animal model system (pg 1005, col. 2).
Gronthos et al (‘229) disclosed wherein a population of about 1x10^5 cultured colony-forming unit cells naturally comprises about 4700 STRO-1(bright), TNAP+ MPCs (syn. 4.7%; e.g. pg 60, table).
Gronthos et al (‘229) disclosed the administration of an enriched population of 5x10^6 STRO-1(bright) stem cells (e.g. pg 74, line 29), which comprises at least 84% STRO-1(bright) cells and TNAP+ cells (e.g. pg 61, lines 26-35).
Thus, the ordinary artisan would have reasonably inferred the administered cell composition comprising at least 5x10^6 cells enriched MPCs comprises at least 4.2x10^6 STRO-1+, TNAP+ cells.
Snable et al disclosed the intravitreal administration (pgs 8-9, joining para, “vitreous-retina interface”) of 3x10^4 cells of an essentially pure therapeutic cell population (pg 8, line 28) at a concentration of 3x10^7 cells/ml (pg 9, lines 24-30; 1 microliter volume injected = 3x10^4 cells) in a rat animal model system. Snable et al also disclosed the administration of 4x10^4 cells, 8x10^4 cells, and 1.2x10^5 cells (Example 3, pg 15, lines 2-3).
Otani et al taught the intravitreal administration of 1x10^5 bone marrow-derived stem cells into the eye of a mouse animal model system (pg 1005, col. 2).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Prior to the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to use human cell composition comprising at least 5% STRO-1+, TNAP+ mesenchymal precursor cells in a method of treating an ocular angiogenesis disease caused by excessive neovascularization, e.g. macular degeneration, so as to reduce at least one symptom of macular degeneration, e.g. such excessive neovascularization. in a human subject’s eye, the method comprising the step of intravitreal administration of at least 1x10^5 cells comprising said at least 5% STRO-1+, TNAP+ MPCs with a reasonable expectation of success because:
i) the ordinary artisan previously recognized the scientific and technical concepts of using CD146+, STRO-l+ mesenchymal precursor cells to treat an ocular angiogenesis disease caused by excessive neovascularization in the eye of a subject, including human subjects, to wit, macular degeneration (Caplan et al);
ii) the ordinary artisan previously recognized the scientific concepts that TNAP+-selected mesenchymal precursor cells naturally express CD146 and STRO-1 during expansion in culture, whereby the cultures initially selected for TNAP+ upregulated STRO-1, presumably reflecting proliferation without spontaneous differentiation (Gronthos et al, pgs 61-62, joining ¶); and
iii) the ordinary artisan previously recognized the scientific concepts that the bone marrow-derived mesenchymal precursor cells are capable of differentiating into vascular endothelial cells and pericytes (Gronthos et al, pg 21, lines 30-32), whereby bone marrow-derived hematopoietic stem cells and endothelial precursor cells are useful for modulating abnormal blood vessel growth in age-related macular degeneration (ARMD) and other retinal degenerations associated with abnormal vasculature, e.g. diabetic retinopathy, whereby the stem cells stably incorporate into developing retinal vasculature, preventing abnormalities of the vessels such as hemorrhage or edema, and this effect might, in fact, alleviate the hypoxia that originally stimulated the neovascularization (Otani et al).
The Examiner notes that the instant independent claim does not actually recite the number of total cells, nor corresponding cell marker phenotype(s), that are actually administered. Rather, the administered cell population is structurally and functionally heterogeneous and undisclosed.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 7, the limitation ‘wherein the stem cells are obtained from bone marrow’ (Claim 7) is considered a product-by-process limitations that are not viewed as positively limiting the claimed product [human cell population comprising STRO-1+, TNAP+ MPC] absent a showing that the process of making recited in Claim 7 imparts a novel or unexpected property to the claimed product, as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the human cell population comprising STRO-1+, TNAP+ MPCs were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
Nevertheless, Gronthos et al (‘229) disclosed wherein the human mesenchymal precursor cells that express a high level of STRO-1 obtained from human bone marrow (e.g. pg 15, lines 5-16).
With respect to Claim 15, Gronthos et al (‘229) disclosed wherein the human mesenchymal precursor cells may be expanded via in vitro culture prior to administration to the subject (e.g. pg 11, line 21; pg 15, lines 18-29, “culture expanded multipotential cells”; pg 76, lines 29-30, “culture-expanded TNAP enriched cells”).
With respect to Claim 16, Gronthos et al (‘229) disclosed wherein the MPCs may be genetically modified by the introduction of exogenous nucleic acids for gene therapy (e.g. pg 11, lines 6-10; pg 30, line 14).
Thus, the instant claims are considered obvious variants of the patented claims.
Conclusion
5. 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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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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