Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 Mar 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s election to Group I, drawn to claims 1-14, without traverse of in the reply filed 17 Jul 2026 is acknowledged. Claims 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-20 are pending. Claims 1-14 are under consideration.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. § 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 4 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The recitation "up to about" in claim 4 renders the claim indefinite. The term "about" includes a number of cardiomyocytes slightly over 1 billion within the claim scope, but the phrase "up to" excludes over 1 billion cells. Therefore, the scope of the claim is unclear because "about" and "up to" create conflicting limitations on the metes and bounds of the claim.
Claim Rejections - 35 USC § 101
35 U.S.C. § 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-7, 9-10, and 12-13 are rejected under 35 U.S.C. § 101 because the claimed invention is directed to a natural product without significantly more. The claims recite an engineered cardiac tissue (ECT). This judicial exception is not integrated into a practical application because the ECT is not markedly distinct from a mammalian heart, which is composed of cardiac tissue with volumetric density of cardiomyocytes within the density recited in the claims. The claims do not include additional elements sufficient to amount to significantly more than the judicial exception because there are no additional elements recited that are not characteristics of a mammalian heart.
Claim 1 recites a density of about 5 million to about 75 million cardiomyocytes (CM)/mL and claim 2 recites a density of about 5 million to about 75 million CM/mL. Bergmann (O. Bergmann, et al., Cell, 2015) teaches measurement of cardiomyocyte density in the human heart across adolescence and adulthood (Abstract). In human adults aged 20 to 73 years, the density of cardiomyocyte (CM) nuclei averages 28,000 ± 7,200 nuclei/mm3, which equates to 28.0 · 106 ± 7.2 · 106 CM nuclei/mL (Results p. 1567 and Fig. 1A). In adults, about 73.6% of CM are mononucleate, about 25.5% of CM are binucleate, and about 1.0% of CM are trinucleate (Results p. 1568 and Fig. 1C). Therefore, the density of cardiomyocytes in the adult heart is about 22.1 · 106 ± 5.7 · 106 CM/mL (within the claimed ranges of about 5 million to about 75 million CM/mL of claim 1 and about 15 million to about 75 million CM/mL of claim 2).
Claim 3 recites a density of about 50 million CM/mL. A human infant heart has about 430,000 ± 72,000 CM nuclei/mm3 shortly after birth and about 80% of CM are mononucleate and about 20% of CM are binucleate (Bergmann Results p. 1567 and Fig. 1A and 1C). Therefore, an infant heart has about 358 · 106 ± 60 · 106 CM/mL. Therefore, between birth and 1 year, an infant heart transiently has about 50 million CM/mL.
Regarding claim 4, the final number of cardiomyocytes in the human heart reaches about 3.2 · 109 ± 5.7 · 109 CM by 1 mo. after birth (Bergmann Results p. 1568). Therefore, the number of cardiomyocytes in the human heart starts at zero in utero and is transiently about 1 billion CM before 1 mo. post-partum (comprising up to about 1 billion CMs, claim 4).
Regarding claim 5, embryonic stem cells undergo stages of proliferation and differentiation during development to generate cardiomyocytes that "express similar cardiac-specific proteins, ion channels and signaling molecules to that of adult cardiomyocytes" in mammals, including humans (A. Sachinidis, et al., Cardiovasc Res, 2003, Abstract and § 2, pp. 279-285). Thus, human embryonic stem cell-derived cardiomyocytes (claim 5) are not markedly different from naturally-occurring cardiomyocytes.
Regarding claims 6-7, a hydrogel is "a network of hydrophilic polymers that absorbs water or biological fluid but does not dissolve" and in a tissue can comprise proteins as the hydrophilic polymers (A. Hillel, et al., Biomedical Polymers, 2007, Introduction § 3.1, p. 57). Therefore, cardiac tissue is a hydrogel. Oken (D.E. Oken and R.J. Boucek, Circ Res, 1957) teaches measurement of collagen content in human myocardium by measuring hydroxyproline content and multiplying the measurements according to the composition of hydroxyproline in collagen (Abstract and Results p. 359). Oken estimates a total of 3.1 g collagen in atria and ventricles and a weight of 249 g for the atria and ventricles, an average of 1.24 g collagen/100 g cardiac tissue. Heart tissue is about 1.053 g/mL (K.C. Vinnakota, et al. Am J Physiol Heart Circ Physiol, 2004, Table 3); therefore, the human heart comprises about 1.31% w/v collagen (substantially comprises, within the claimed range of about 1 to about 8 mg/mL, claim 7). Note that the specification does not provide a limiting definition for the term "substantially". Under the broadest reasonable interpretation, "comprising a hydrogel substantially comprised of collagen" is interpreted to mean that collagen is present at a sufficiently high concentration to have any measurable functional effect on cardiac tissue. Oken further teaches that the concentration of collagen in human myocardium is physiologically and pathologically significant (substantially comprises, claim 6) (Abstract).
Regarding claims 9-10, Zhou (P. Zhou and W.T. Pu, Circ Res, 2016) teaches that mouse and rat hearts have a similar density of cardiomyocytes but differ in proportion of cardiomyocytes to non-myocyte cells (Introduction p. 368). Cells in mouse hearts comprise 32% cardiomyocytes and 13% cardiac fibroblasts (CF), therefore the number of CF is about 42% of the number of CM (Zhou p. 369) (within the claimed range of about 5% to about 50%, claim 10).
Regarding claims 12-13, a mouse heart has a rostral-caudal length of 5 to 8 mm (M.L. Lindsey, et al. Am J Physiol Heart Circ Physiol, 2018, p. H734). Using a sphere to approximate volume, the mouse heart is about 49 to about 200 μL (within the claimed range of about 25 μL to about 25 mL).
The Office published the guidance document entitled 2014 Interim Guidance on Patent Subject Matter Eligibility (Interim Eligibility Guidance), published 16 Dec 2014. Step 2A was revised to include two prongs (Federal Register / Vol. 84, No. 4 / 07 Jan 2019).
Analysis is as follows:
Step 1: Is the claim drawn to one of the statutory categories of invention (a process, a machine, a manufacture, and/or a composition of matter)?
Step 1: The claim is directed to a composition of matter (an engineered cardiac tissue).
Step 1: Yes.
Step 2A, Prong One: Does the claim recite a judicial exception (a law of nature, a natural product/phenomenon, or an abstract idea)?
Step 2A, Prong One: The composition of matter (an engineered cardiac tissue) is directed to a natural product. The claim recites a composition that is not markedly different from a mammalian heart.
Step 2A, Prong One: Yes.
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into practical application of the exception?
Step 2A, Prong Two: This exception is not integrated into practical application because the claim does not recite additional elements that integrate the judicial exception into practical application. The claims merely recite elements found naturally in a mammalian heart. See MPEP § 2106.05(h).
Step 2A, Prong Two: No.
Step 2B: Does the claim recite additional elements that individually or in combination amount to significantly more than the judicial exception (i.e., whether the additional elements provide an inventive concept)?
Step 2B: The claims merely recite elements found in a mammalian heart, and therefore, there are no additional elements that could amount to significantly more.
Step 2B: No.
The markedly different characteristics analysis performed in Step 2A, Prong One is a comparison of the nature-based product limitation to its naturally occurring counterpart in its natural state. Markedly different characteristics can be expressed as the product’s structure, function, and/or other properties. Product of nature exceptions include both naturally occurring products and non-naturally occurring products that lack markedly different characteristics from any naturally occurring counterpart. See MPEP § 2106.04(b)(II). If the claim recites a nature-based product limitation that does not exhibit markedly different characteristics, the claim is directed to a product of nature exception, and the claim will require further analysis to determine eligibility based on whether additional elements add significantly more to the exception. In accordance with this analysis, an engineered cardiac tissue, for example, is eligible when there is a resultant change in characteristics sufficient to show a marked difference from a mammalian heart. It is concluded here that the claimed an engineered cardiac tissue is not markedly different from its naturally occurring counterpart, a mammalian, as the claim does not recite structural limitations that distinguish the claimed composition from its naturally occurring counterpart.
The Supreme Court has identified several considerations for determining whether a claim with additional elements amounts to significantly more than the judicial exception itself. Limitations that may qualify as significantly more when recited in a claim with a judicial exception include: improvements to another technology or technical field; improvements to the functioning of the computer itself; applying the judicial exception with, or by use of, a particular machine; effecting a transformation or reduction of a particular article to a different state or thing; adding a specific limitation other than what is well-understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application; or other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
Limitations that were found not to be enough to qualify as significantly more when recited in a claim with a judicial exception include: adding the words ‘apply it’ (or an equivalent) with the judicial exception; mere instructions to implement an abstract idea on a computer; simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception; adding insignificant extra-solution activity to the judicial exception; or generally linking the use of the judicial exception to a particular technological environment or field of use.
In the instant case, the limitations of the claims do not impose limits on the scope of the claim such that the engineered cardiac tissue is markedly different from a naturally occurring product. Accordingly, based on analysis of the claim as a whole, the claims do not recite additional elements adding significantly more than the judicial exception and are thus rejected under 35 U.S.C. § 101 because the claimed invention is not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. § 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 6-7, 9-10, and 12-13 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Bergmann (O. Bergmann, et al., Cell, 2015) and evidenced by Hillel (A. Hillel, et al., Biomedical Polymers, 2007), Oken (D.E. Oken and R.J. Boucek, Circ Res, 1957), Vinnakota (K.C. Vinnakota, et al. Am J Physiol Heart Circ Physiol, 2004), Zhou (P. Zhou and W.T. Pu, Circ Res, 2016), and Lindsey (M.L. Lindsey, et al. Am J Physiol Heart Circ Physiol, 2018).
Regarding claims 1-2, Bergmann teaches measurement of cardiomyocyte density in the human heart across adolescence and adulthood (Abstract). In human adults aged 20 to 73 years, the density of cardiomyocyte (CM) nuclei averages 28,000 ± 7,200 nuclei/mm3, which equates to 28.0 · 106 ± 7.2 · 106 CM nuclei/mL (Results p. 1567 and Fig. 1A). In adults, about 73.6% of CM are mononucleate, about 25.5% of CM are binucleate, and about 1.0% of CM are trinucleate (Results p. 1568 and Fig. 1C). Therefore, the density of cardiomyocytes in the adult heart is about 22.1 · 106 ± 5.7 · 106 CM/mL within the claimed ranges of about 5 million to about 75 million CM/mL of claim 1 and about 15 million to about 75 million CM/mL of claim 2).
Regarding claim 3, a human infant heart has about 430,000 ± 72,000 CM nuclei/mm3 shortly after birth and about 80% of CM are mononucleate and about 20% of CM are binucleate (Bergmann Results p. 1567 and Fig. 1A and 1C). Therefore, an infant heart has about 358 · 106 ± 60 · 106 CM/mL. Therefore, between birth and 1 year, an infant heart transiently has about 50 million CM/mL.
Regarding claim 4, the final number of cardiomyocytes reaches about 3.2 · 109 ± 5.7 · 109 CM by 1 mo. after birth (Bergmann Results p. 1568). Therefore, the number of cardiomyocytes in the human heart starts at zero in utero and is transiently about 1 billion CM before 1 mo. post-partum.
Regarding claims 6-7, Hillel teaches that a hydrogel is "a network of hydrophilic polymers that absorbs water or biological fluid but does not dissolve" and in a tissue can comprise proteins as the hydrophilic polymers (Introduction §3.1, p. 57). Therefore, cardiac tissue is a hydrogel. Oken teaches measurement of collagen content in human myocardium by measuring hydroxyproline content and multiplying the measurements according to the composition of hydroxyproline in collagen (Abstract and Results p. 359). Oken estimates a total of 3.1 g collagen in atria and ventricles and a weight of 249 g for the atria and ventricles, an average of 1.24 g collagen/100 g cardiac tissue. Heart tissue is about 1.053 g/mL (Vinnakota Table 3 and Discussion p. H1748); therefore, the human heart comprises about 1.31% w/v collagen (substantially comprises, within the claimed range of about 1 to about 8 mg/mL, claim 7). Note that the specification does not provide a limiting definition for the term "substantially". Under the broadest reasonable interpretation, "comprising a hydrogel substantially comprised of collagen" is interpreted to mean that collagen is present at a sufficiently high concentration to have any measurable functional effect on cardiac tissue. Oken further teaches that the concentration of collagen in human myocardium is physiologically and pathologically significant (substantially comprises, claim 6) (Abstract).
Regarding claims 9-10, Zhou teaches that mouse and rat hearts have a similar density of cardiomyocytes but differ in proportion of cardiomyocytes to non-myocyte cells (Introduction p. 368). Cells in mouse hearts comprise 32% cardiomyocytes and 13% cardiac fibroblasts (CF), therefore the number of CF is about 42% of the number of CM (Zhou p. 369) (within the claimed range of about 5% to about 50%, claim 10).
Regarding claims 12-13, a mouse heart has a rostral-caudal length of 5 to 8 mm (Lindsey p. H733). Using a sphere to approximate volume, the mouse heart is about 49 to about 200 μL (within the claimed range of about 25 μL to about 25 mL).
Claims 1-3 and 5-14 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Rupert 1 (C.E. Rupert, et al. Stem Cells International, 2020) and as evidenced by Rupert 2 (C.E. Rupert, et al., PLoS One, 2020, cited in the IDS filed 17 Nov 2025) and Munarin (F. Munarin, et al. Tissue Eng Part C Methods, 2017, cited in the IDS filed 17 Nov 2025).
Regarding claims 1-2, Rupert 1 discloses an engineered cardiac tissue (ECT) comprising 16 · 106 human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (hiPSC-CM)/mL (within the claimed ranges of about 5 million to about 75 million CM/mL of claim 1 and about 15 million to about 75 million CM/mL of claim 2) (Methods § 2.5, p. 3).
Regarding claim 3, Rupert 2 references Rupert 1 as the method for forming the ECT (Rupert 2 Materials and Methods p. 3). The ECT undergoes compaction during one week of culture to about a third of its original cross-sectional area, a three-fold increase in density (Rupert 2 Results p. 8). Therefore, the density of CM in the ECT disclosed by Rupert 1 increases from about 16 · 106 to about 48 · 106 hiPSC-CM/mL (about 50 million CM/mL).
Regarding claim 5, the cardiomyocytes disclosed by Rupert 1 are derived from human iPSC (Methods § 2.5, p. 3).
Regarding claims 6-7, the ECT disclosed by Rupert 1 is formed by mixing 50% v/v rat tail collagen I to produce a hydrogel with final density of 1.25 mg/mL at the time of molding (a hydrogel substantially comprising collagen, within the claimed range of about 1 to about 8 mg/mL collagen) (Methods § 2.5, p. 3). Note that the specification does not provide a limiting definition for the term "substantially". Under the broadest reasonable interpretation, "comprising a hydrogel substantially comprised of collagen" is interpreted to mean that collagen is present at a sufficiently high concentration to have any measurable functional effect on the ECT.
Regarding claim 8, Rupert 2 references Rupert 1 as the method for forming the ECT (Rupert 2 Materials and Methods p. 3). The ECT undergoes compaction during one week of culture to about a third of its original cross-sectional area, a three-fold increase in density (Rupert 2 Results p. 8). Therefore, the density of collagen in the ECT disclosed by Rupert 1 increases from about 1.25 mg/mL at the time of molding to about 3.75 mg/mL after one week in culture (about 3.5 mg/mL).
Regarding claims 9-11, one embodiment of the ECT disclosed by Rupert 1 further comprises human cardiac fibroblasts (hCF) at a cell density of 5% of the number of hiPSC-CM (Methods § 2.5, p. 3 and Results § 3.2, p. 4).
Regarding claims 12-14, Rupert 1 discloses seeding 106 hiPSC-CM to a final density of 16 · 106 hiPSC-CM/mL to mold the ECT (Methods § 2.5, p. 3). Therefore, the ECT has a starting volume of 62.5 μL on day 0 (within the claimed range of about 25 μL to about 25 mL). Rupert discloses forming the ECT in a mold described in Munarin and shows that the ECT have holes at the ends indicating formation in a mold comprising posts (Methods § 2.5, p. 3 and Fig. 2a-2d). Munarin discloses molds for forming ECT comprising posts at the end to facilitate mechanical testing that correspond to the geometry of the ECT in Rupert Fig. 2a-2d (Fig. 1E part i). Munarin further discloses that ECT formed in the molds are a suitable size to implant in 8-week-old male Sprague-Dawley rats (a volume that is surgically implantable in a living animal, claim 12) (Materials and Methods p. 314).
Conclusion
No claim is allowed.
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Eric B Wright, PhD
Examiner
Art Unit 1632
/Eric B Wright/Examiner, Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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