Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 16, 2025 has been entered.
Detailed Action
This action is in response to the papers filed June 16, 2025.
Amendments
Applicant's response and amendments, filed June 16, 2025, to the prior Office Action is acknowledged. Applicant has cancelled Claims 2-5, 8-12, and 14, amended Claims 1, 6-7, and 15-16, and withdrawn Claim 13.
Claims 1, 6-7, 13, and 15-16 are pending.
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.
Election/Restrictions
Applicant has elected with traverse the following species, wherein the angiogenesis-related disease to be treated is macular degeneration, as recited in Claims 2-6.
The anti-cancer agent species is moot because it is directed to a non-elected invention.
Response to Arguments
Applicant argues that there is no undue search burden.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner explained in the Requirement for Restriction that a search for wet age-related macular degeneration would not be co-extensive with a search for cancer or a benign tumour in combination with an anti-cancer agent. Further, a reference rendering diabetic retinopathy as anticipated or obvious over the prior art would not necessarily also render rubeosis as anticipated or obvious over the prior art. Because these inventions are distinct for reasons given above, and because a search of one does not necessarily overlap with that of another, it would be unduly burdensome for the examiner to search and examine all the subject matter being sought in the presently pending claims and thus, restriction for examination purposes as indicated is proper.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1, 6-7, 13, and 15-16 are pending.
Claim 13 is pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 6-7, and 15-16 are under consideration.
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
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
1. Claims 1, 6-7, and 15-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 has been amended to recite a method of treating macular degeneration or diabetic retinopathy in a human subject, the method comprising the step of administering by intravitreal injection an effective amount of a pharmaceutical composition comprising at least 5% STRO-1+, TNAP+ mesenchymal precursor cells (MPCs),
wherein the amount of human cell population is sufficient to reduce or eliminate at least one symptom of macular degeneration or diabetic retinopathy.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
While it is clear that the referenced human cell population is to comprise at least 1x10^5 cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs, the claim fails to recite the actual human cell population amount that is to be administered intravitreally.
To put it another way, the claim does not require intravitreal administration of at least 1x10^5 human cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs. Rather, the cell number to be administered may be as few as 20 (1 MPC), 40 (2 MPCs), 100 (5 MPCs), 1x10^3 (50 MPCs), 1x10^4, or more than 1x10^6, 1x10^7, 1x10^8, etc…
Mere reference to a pharmaceutical stock formulation, comprises at least 1x10^5 cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs, does not inform the ordinary artisan as to the actual cell number of said pharmaceutical stock formulation that is to actually be administered.
The phrase “an effective amount” itself denote(s) that there is an amount of the pharmaceutical composition (syn. total cell number) comprising at least 5% STRO-1+, TNAP+ MPCs, that, upon administration to the subject, is not, in fact, “a [therapeutically] effective amount” to reduce or eliminate at least one symptom of macular degeneration or diabetic retinopathy.
The claims are broad for reasonably encompassing an enormous genus of cell numbers (syn. dosages) that may be administered to the subject.
The specification discloses, at best, intravitreal administration of 1x10^5 cells to the eyes of rats (Example 2, pg 37, line 8). While Example 2 discloses establishing a primary culture of the TNAP+ cells, the specification fails to disclose what percentage of these TNAP+ cells are, in fact, STRO-1+, as required by the independent claim, nor the culture medium conditions in which the TNAP+ cells are expanded, nor the resulting % of STRO-1+, TNAP+ MPCs present in the thus-expanded cell populations which are then used for administration. Instant specification working example fails to disclose what % of the TNAP+ enriched cell population is actually present. Instant specification fails to disclose what % of the TNAP+ enriched cell population is, in fact, STRO-1+.
The claims are directed to a heterogeneous population of structurally, phenotypically, and functionally different cell types, for which it is unclear what number of cells, and their corresponding identities, is/are required to be present in order to be a “therapeutically effective amount” sufficient to treat the broad genus of angiogenesis-related diseases.
The claims fail to recite, and the specification fails to disclose, a first STRO-1+, TNAP+ MPC dosage administered that is necessarily and predictably able to prevent blindness, or at least one undisclosed symptom associated with blindness, macular degeneration, and/or diabetic retinopathy, in a subject, as opposed a second STRO-1+, TNAP+ MPC dosage administered that is unable to increase retinal thickness, or reduce or eliminate at least one undisclosed symptom associated with blindness, macular degeneration, and/or diabetic retinopathy, in a subject, for example.
The recitation implies a genus of unrecited and undisclosed total human cell numbers and a genus of unrecited and undisclosed total STRO-1+, MPC+ MPC cell numbers, to be administered intravitreally to the subject, as well as a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, result-effective variables dependent upon different parameters, thereby rendering the claim indefinite.
Failure to provide clear-cut indication of claim scope because the functional language is not sufficiently precise and definite resulting in no boundaries on the claim limitation. The ordinary artisan would not know from the claims what specific type of cell, and thus corresponding cell number, is/are to be administered via the corresponding route, in order to be predictably sufficient to be therapeutically effective to treat the genus of angiogenesis-related diseases and disorders.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Appropriate correction is required.
Response to Arguments
Applicant argues that the amendments to Claim 1 render the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. While it is clear that the referenced human cell population is to comprise at least 1x10^5 cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs, the claim fails to recite the actual total human cell population amount and the actual total STRO-1+, TNAP+ MPC amount that is/are to be administered intravitreally.
To put it another way, the claim does not require intravitreal administration of at least 1x10^5 human cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs (syn. just 5000 STRO-1+, TNAP+ MPCs).
Mere reference to a pharmaceutical stock formulation, comprises at least 1x10^5 cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs, does not inform the ordinary artisan as to the actual cell number of said pharmaceutical stock formulation that is to actually be administered.
The Examiner suggest amending Claim 1 to recite, e.g. “the method comprising administering to the human subject by intravitreal injection a human cell population comprising at least 1x10^5 cells, wherein at least 5% of said human cell population are STRO-1+, TNAP+ MPCs”.
2. Claims 1, 6-7, and 15-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite a method of treating macular degeneration or diabetic retinopathy in a human subject, the method comprising the step of administering by intravitreal injection an effective amount of a pharmaceutical composition comprising at least 5% STRO-1+, TNAP+ mesenchymal precursor cells (MPCs),
wherein the amount of human cell population is sufficient to reduce or eliminate at least one symptom of macular degeneration or diabetic retinopathy.
While it is clear that the referenced human cell population is to comprise at least 1x10^5 cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs, the claim fails to recite the actual human cell population amount that is to be administered intravitreally.
To put it another way, the claim does not require intravitreal administration of at least 1x10^5 human cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs. Rather, the cell number to be administered may be as few as 20 (1 MPC), 40 (2 MPCs), 100 (5 MPCs), 1x10^3 (50 MPCs), 1x10^4, or more than 1x10^6, 1x10^7, 1x10^8, etc…
Mere reference to a pharmaceutical stock formulation, comprises at least 1x10^5 cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs, does not inform the ordinary artisan as to the actual cell number of said pharmaceutical stock formulation that is to actually be administered.
The phrase “an effective amount” itself denote(s) that there is an amount of the pharmaceutical composition (syn. total cell number) comprising at least 5% STRO-1+, TNAP+ MPCs, that, upon administration to the subject, is not, in fact, “a [therapeutically] effective amount” to reduce or eliminate at least one symptom of macular degeneration or diabetic retinopathy.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The Examiner incorporates herein the above U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in [application]. Thus, [application] does not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
The specification disclose in boilerplate form that the MPCs may be present in the cell population in an amount of:
i) 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 95% (pg 14, lines 29-30);
ii) 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% (pg 15, lines 13-14); or
iii) 40% or 45% (pg 14, lines 10-11).
However, as discussed previously, while Example 2 discloses establishing a primary culture of the TNAP+ cells, the specification fails to disclose what percentage of these TNAP+ cells are, in fact, STRO-1+, as required by the independent claim, nor the culture medium conditions in which the TNAP+ cells are expanded, nor the resulting % of STRO-1+, TNAP+ MPCs present in the thus-expanded cell populations which are then used for administration. Instant specification working example fails to disclose what % of the TNAP+ enriched cell population is actually present. Instant specification fails to disclose what % of the TNAP+ enriched cell population is, in fact, STRO-1+.
The originally filed application and claims fail to provide sufficient blazemarks to arrive at the instantly claimed invention directed to a combination of different method parameters, including the subject, the disease(s) to be treated, the type of cell pharmaceutical formulary, the number of cells of said cell pharmaceutical formulary to be administered to the subject, the route of administration, and the resulting phenotype(s) to be achieved by the claimed method.
Failure to provide clear-cut indication of claim scope because the functional language is not sufficiently precise and definite resulting in no boundaries on the claim limitation. The ordinary artisan would not know from the claims what specific type of cell, and thus corresponding cell number, is/are to be administered in order to be predictably sufficient to reduce or eliminate at least one symptom of macular degeneration or diabetic retinopathy.
Gronthos et al (J. Bone and Mineral Res. 14(1): 47-56, 1999; of record) evidences that mere presence of TNAP does not strictly correlate with or establish expression of STRO-1. Rather, as shown in Figure 1, only about 2.4% of the cells that are TNAP+ may also be STRO-1+.
Bara et al (Stem Cells 32: 1713-1723, 2014; of record) is considered relevant art for having taught that those of ordinary skill in the art immediately recognize that in vitro expansion of MSC “causes dramatic changes in MSC phenotype which has very significant implications for the development of effective therapies” (Abstract). MSCs appear to lose multipotency and display a propensity toward osteogenic differentiation (pg 1716, col. 1).
The instant specification cites Gronthos et al (Blood 85(4): 929-940, 1995; pg 32, line 25; of record) as support for expanding TNAP+ cells; however, Gronthos et al (1995) taught that the number of STRO-1 cells in the population can dramatically change, depending upon the growth factors, or combination(s) thereof, used to expand the cells, as evidenced by the colony forming abilities of the thus-expanded cell populations (Figures 9-10). The specification also cites Gronthos et al (J. Cell Science 116: 1827-1835, 2003; of record) as support for expanding TNAP+ cells; however, Gronthos et al (2003) taught that the number of STRO-1 cells in the population can dramatically change, whereby even with a starting cell population comprising 73% STRO-1 bright cells (pg 1829, col. 2), after expansion, the cell population may only comprise a minor subpopulation, e.g. as little as 3% (a 96% loss) (pg 1831, col. 2).
Instant specification discloses having expanded the TNAP+ cells in a culture medium as per Gronthos et al (1995) (pg 33, lines 10-12), wherein Gronthos et al (1995) taught the culture medium comprises EGF and/or bFGF (syn. FGF-2) (pg 932, col. 1, Figure 3).
Short et al (Arch. Medical Res. 34: 565-571, 2003; of record) is considered relevant prior art for having taught that culturing STRO-1+ CFU-F marrow stromal cells in a culture medium comprising EGF or FGF-2 (syn. bFGF) reduces the expression of alkaline phosphatase (syn. TNAP; pgs 566-567, joining ¶). Thus, one of ordinary skill in the art reading the instant specification would immediately recognize that although the initial population enriched for at least 10% of the cells being TNAP+ would substantially, if not entirely, lose expression of the TNAP+ marker during expansion practiced in the instant working examples. The Examiner further notes that Gronthos et al (1995) fails to teach the % cells that are expressing STRO-1, nor CD146+, after the culturing steps. So, here, too, Gronthos et al (1995) is uninformative as to the resulting composition of cell type(s) present in the heterogeneous, structurally undisclosed, thus-expanded cell population.
Kortesidis et al (Blood 105(10): 3793-3801, May 15, 2005; available online January 27, 2005; of record) is considered relevant prior art for having taught that bone marrow-derived stromal cells naturally express high levels of STRO-1 and CD146; however, the STRO-1bright, CD146+ stromal cells “revealed considerable differences in the gene expression profiles of these precursor cells when compared with culture-expanded BMSSCs” (pg 3793, col. 2), with “a down-regulation of the early stromal marker, STRO-1, over prolonged ex vivo expansion” (pg 3794, col. 1).
De Bari et al (Arthritis & Rheumatism 54(4): 1209-1221, April 2006; available online March 30, 2006; of record) is considered relevant prior art for having taught expansion of multipotent stromal cells in tissue culture, said cell population comprising periosteal cells being CD146+, but the thus-expanded cells lack TNAP expression (pg 1212, col. 2, “alkaline phosphatase… undetectable in expanded periosteal cells”; Figure 1d).
The specification discloses, at best, intravitreal administration of 1x10^5 cells to the eyes of rats (Example 2, pg 37, line 8). While Example 2 discloses establishing a primary culture of the TNAP+ cells, the specification fails to disclose what percentage of these TNAP+ cells are, in fact, STRO-1+, as required by the independent claim, nor the culture medium conditions in which the TNAP+ cells are expanded, nor the resulting % of STRO-1+, TNAP+ MPCs present in the thus-expanded cell populations which are then used for administration. Instant specification working example fails to disclose what % of the TNAP+ enriched cell population is actually present. Instant specification fails to disclose what % of the TNAP+ enriched cell population is, in fact, STRO-1+
There is no evidence that one of ordinary skill in the art would be able to reasonably extrapolate the cell dosage required to achieve therapeutic efficacy of a first heterogeneous cell population of unknown composition that is not STRO-1+, TNAP+, MPCs, nor comprises, if any, of an unknown % of STRO-1+, TNAP+, MPCs, to a necessarily, sufficiently, and predictably arrive at a cell dosage therapeutic efficacy of a second, distinctly different cell population that is not STRO-1+, TNAP+, MPCs, nor comprises, if any, of an unknown % of STRO-1+, TNAP+, MPCs. Rather, Applicant leaves it to the ordinary artisan to discover for themselves the effective amount of a cell composition composed of structurally and functionally unknown cell types, the corresponding cell number dosage, and timing of administration (pg 24, para 1), disclosing generic cell number concentrations, ranging from 5x10^5 to 5x10^7 cells/ml (pg 24, para 2).
It is clear that the thus-expanded cell population is heterogeneous, as was the starting cell population prior to enrichment. However, the instant specification fails to disclose, and the instant claims fail to recite, what % of the thus-expanded cell population is, in fact, STRO-1+, TNAP+ non-hematopoietic mesenchymal precursor cells. Essentially, one does not even know the identity of the thus-expanded cell population disclosed by the instant application, nor recited in the instant claims.
The method then requires administering to the subject via an enormous genus of anatomically distinct routes some number of the thus-expanded, structurally/phenotypically undisclosed, cell population, whereby said number is to be “sufficient to treat macular degeneration”. However, neither the claims nor the specification identify the specific cell type that achieves the required functional property “sufficient to treat macular degeneration”.
Thus, it is unclear if Applicant is referring to a sufficient number of the structurally and functionally undisclosed cells non-TNAP+ and/or non-STRO-1+, non(?)-MPCs, or if Applicant is referring to a sufficient number of the at least 10% STRO-1+, TNAP+ MPCs.
The claims do not actually recite the cell number that is to be administered. Furthermore, as discussed supra, because both the enriched, pre-expanded cell population and the post-expanded cell population of unknown and undisclosed structure/function phenotype are each heterogeneous, it is unclear which cell type, the STRO-1+, TNAP+, MPCs or the non-TNAP+ and/or non-STRO-1+ non(?)-MPCs is present in the cell population that is to achieve the functional property “sufficient to treat macular degeneration”, as required by the independent claim.
The claims fail to recite, and the specification fails to disclose, a first STRO-1+, TNAP+ MPC dosage administered that is necessarily and predictably able to prevent blindness, or at least one undisclosed symptom associated with blindness, macular degeneration, and/or diabetic retinopathy, in a subject, as opposed a second STRO-1+, TNAP+ MPC dosage administered that is unable to increase retinal thickness, or reduce or eliminate at least one undisclosed symptom associated with blindness, macular degeneration, and/or diabetic retinopathy, in a subject, for example.
"The claimed invention as a whole may not be adequately described if the claims require an essential or critical element which is not adequately described in the specification and which is not conventional in the art", "when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus", "in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus''. MPEP §2163
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
The prior art evidences that the STRO-1 and TNAP cell markers do not positively correlate with each other. The prior art evidences that both the STRO-1 and TNAP cell marker expression profiles change over time, typically decreasing, when expanding a starting cell population in tissue culture. Instant claims fail to recite a specific culture condition (parameter variable) and length of time (parameter variable) for which the starting heterogeneous cell population is to be expanded in culture such that the thus-expanded, resulting cell population has the instantly recited cell marker phenotype expression profile. Thus, knowledge of a starting heterogeneous cell population does not predictably inform the ordinary artisan as to the % cell marker phenotype(s) expression profile of a resulting, thus-expanded (indefinitely expanded?), heterogeneous cell population comprising non-TNAP+ and/or non-STRO-1 non(?)-MPCs, nor the corresponding functionality(ies) of the structurally undisclosed heterogeneous cell population.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, Applicant seeks to monopolize an entire class of pharmaceutical compositions comprising a heterogeneous cell population comprising an unrecited amount STRO-1+ MPCs for the treatment of an enormous genus of angiogenesis-related diseases/disorders/conditions.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
The specification fails to make up for the deficiencies of the global scientific community.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of, nor enabling for, the nexus between the broad genus of cellular pharmaceutical compositions comprising an enormous genus of variable amounts of STRO-1+ MPCs, e.g. as little as 5%, the enormous genus of cell dosages, in a therapeutically effective amount, respectively, so as to necessarily and predictably achieve real-world and clinically meaningful therapeutic result(s) of treating macular degeneration and/or diabetic retinopathy at the time the application was filed.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant argues that the amendments to Claim 1 render the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. While it is clear that the referenced human cell population is to comprise at least 1x10^5 cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs, the claim fails to recite the actual human cell population amount that is to be administered intravitreally.
To put it another way, the claim does not require intravitreal administration of at least 1x10^5 human cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs. Rather, the cell number to be administered may be as few as 10, 100, 1x10^3, 1x10^4, or more than 1x10^6, 1x10^7, 1x10^8, etc…
Mere reference to a pharmaceutical stock formulation, comprises at least 1x10^5 cells, of which at least 5% are to be STRO-1+, TNAP+ MPCs, does not inform the ordinary artisan as to the actual cell number of said pharmaceutical stock formulation that is to actually be administered.
The Examiner suggest amending Claim 1 to recite, e.g. “the method comprising administering to the human subject by intravitreal injection a human cell population comprising at least 1x10^5 cells, wherein at least 5% of said human cell population are STRO-1+, TNAP+ MPCs”.
3. The prior rejection of Claims 1-7, 9, 11-12, and 15-16 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in light of Applicant’s amendments to the claims.
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).
4. The prior rejection of Claims 1-5, 7, and 11 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Caplan et al (WO 04/084950; of record in IDS) and Baksh et al (U.S. 2004/0137612; of record in parent application 12/309,158) is withdrawn in light of Applicant’s amendment to the independent claim as a whole, necessitating new grounds of rejection.
5. The prior rejection of Claims 1-6 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Caplan et al and Baksh et al, as applied to Claims 1-5, 7, and 11, and in further view of Snable (WO 98/34485; of record in parent application 15/788,438) and Hamdi et al (Front. Biosci. 8:e305-14, 2003; abstract only; of record in parent application 12/309158) is withdrawn for reasons discussed above.
6. The prior rejection of Claims 7, 9, 11-12, and 15-16 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Caplan et al, Baksh et al, Snable, and Hamdi et al, as applied to Claims 1-7, and 11, and in further view of Gronthos et al (U.S. 2005/0019911; of record in parent applications 12/309,158 and 15/788,438; hereafter Gronthos-1) and Gronthos et al (WO 06/108229; filed April 12, 2006; priority to April 12, 2005; of record in parent application 15/788,438; hereafter Gronthos-2) is withdrawn for reasons discussed above.
7. 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).
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 ¶).
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 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).
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 i