Obviousness

Under 35 U.S.C. § 103, an invention is considered obvious if "the differences between the claimed invention 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 the subject matter pertains." This analysis considers the scope and content of the prior art, the differences between the prior art and the claims, the level of ordinary skill in the art, and any secondary considerations of non-obviousness.

The core problem addressed by US7846728, as explicitly stated in its background, is the significant limitation of developing large organs or tissues (greater than a few millimeters) using tissue engineering due to the "lack of a well developed vascular supply for organogenesis," [cite: A short list of persistent problems in this area include:] leading to issues like "tissue resorption" [cite: A short list of persistent problems in this area include:] and "loss of cell function." [cite: A short list of persistent problems in this area include:] The patent emphasizes the need for a "vascularized scaffold with a complete vascular bed." [cite: In an effort to design a three dimensional biodegradable scaffold which could overcome the barrier of developing large organs with tissue engineering, the present inventors hypothesized that a vascularized scaffold with a complete vascular bed would be needed to overcome this barrier.]

A person having ordinary skill in the art (PHOSITA) in tissue engineering would be aware of these fundamental challenges and the known properties of various tissues and scaffolds.

Obviousness of Claim 1:
Claim 1 describes "An implant comprising: a three dimensional scaffold shell having an interior and an exterior; and a tissue matrix deposited in the interior of said scaffold shell comprising multiple folds of vascularized omentum in combination with excised fat tissue inserted between said folds of said omentum, wherein said scaffold is comprised of a material that is different from said tissue matrix."

1. Three-dimensional scaffold shell: Prior art clearly teaches the use of three-dimensional scaffolds. For instance, Sahatjian et al. (US Pat. appl. 20040126405) proposed "a three dimensional cell scaffold either as a sheet or a tube configured into various shapes." [cite: a later application] Similarly, Yelick et al. (US Pat. appl. 20020119180 A1) constructed a "biodegradable polymer scaffold molded in the shape of a tooth." [cite: Yelick et al.] Atala et al. (US Pat. appl. 20070059293 A1) also used a "biodegradable bladder-shaped scaffold." [cite: Recently, a successful human clinical trial has been reported]
2. Vascularized omentum: The use of omentum as a source of vasculature for tissue engineering was well-established in the prior art. Vacanti et al. (U.S. Pat. No. 5,804,178, U.S. Pat. No. 5,770,193, and U.S. Pat. No. 5,759,830) reported "implanting sheets of cell-matrix structure adjacent to mesentery, omentum, or peritoneum tissue." [cite: Vacanti et al. also reported the idea of implanting sheets of cell-matrix structure adjacent to mesentery, omentum, or peritoneum tissue] Yelick et al. placed scaffolds "onto the omentum of rats," [cite: Yelick et al.] and Grikscheit et al. (US Pat. appl. 20030129751) used scaffolds "sutured to the rat's omentum to make new colonic tissue." [cite: a later application] Atala et al. implanted scaffolds "covered with omentum." [cite: Recently, a successful human clinical trial has been reported] The patent itself acknowledges this, stating: "In all of the above studies, the omentum was used as a single layer attached to one side of a flat scaffold, or wrapped around a three-dimensional scaffold." [cite: Recently, a successful human clinical trial has been reported]
3. Excised fat tissue: The problem of fat graft resorption due to inadequate vascularization was a known issue. The patent's background states that "fat grafts larger than a few mm in diameter are well documented of undergoing resorption over time. Except for small volume fat grafting transferred into multiple well vascularized tunnels, most fat grafts undergo partial resorption." [cite: a list of the tissues which have been autografted with well documented resorption over time] This clearly highlights the need for improved vascularization for fat tissue.
4. "Multiple folds of vascularized omentum in combination with excised fat tissue inserted between said folds of said omentum": Given the prior art's recognition of omentum as a vascular source and the explicit problem of fat graft resorption due to lack of vascularization, a PHOSITA would be motivated to maximize the vascular supply to the fat tissue. The prior art demonstrates methods of placing scaffolds adjacent to or wrapped with omentum. To improve upon these methods and enhance vascularization for larger tissue constructs or fat grafts prone to resorption, a PHOSITA would find it obvious to increase the surface area of contact between the omentum and the fat cells. Creating "multiple folds" of omentum and inserting fat tissue between these folds within a scaffold would be an obvious engineering design choice to achieve maximal intimate contact and, thus, superior vascularization, directly addressing the stated problems of limited tissue size and resorption. The patent itself articulates this motivation by stating that "The scaffold interior is designed in order to accommodate multiple layers of omentum, in contact with autologous cells suspended in nutrient-containing matrix." [cite: the present invention thus provides a novel three dimensional biodegradable scaffold capable for use in developing large organs with tissue engineering.]
5. Scaffold material different from tissue matrix: This is inherent in combining a synthetic or naturally derived scaffold (e.g., polymer, collagen as taught by Grikscheit and Atala) with biological tissue (omentum, fat).

Combination: A PHOSITA would be motivated to combine the three-dimensional scaffold teachings of Sahatjian et al. or Yelick et al. with the extensive teachings on using omentum for vascularization from Vacanti et al., Yelick et al., Grikscheit et al., and Atala et al. The well-known problem of fat graft resorption, as discussed in the patent's background, would further motivate this combination. The need to overcome the "barrier of developing large organs with tissue engineering" [cite: the field of the present invention] by enhancing vascular supply would lead a PHOSITA to design a scaffold system that maximizes the interaction between the omentum and the tissue to be vascularized (e.g., fat). Inserting the fat tissue between multiple folds of the vascularized omentum within the scaffold is an obvious optimization to achieve this goal, with a reasonable expectation of success given the known properties of omentum and the physiological need for vascularization.

Obviousness of Claim 2:
Claim 2 specifies the implant as a "breast implant."
Motivation: Vacanti et al. (U.S. Pat. No. 5,716,404) explicitly proposed "breast tissue engineering" by "implanting a tissue expander device into the breast" with dissociated cells in a biodegradable matrix. [cite: The Harvard University group led by Vacanti proposed placing dissociated cells into a biodegradable matrix to be implanted with a tissue expander device into the breast] While that method had issues due to lack of vascularization, the patent also highlights ongoing problems with "autologous fat grafting for cosmetic breast augmentation" due to "fat necrosis" and difficulties in "future cancer detection." [cite: As a consequence, fat grafting for breast augmentation may make future cancer detection difficult. For this reason, autologous fat grafting for cosmetic breast augmentation has been discouraged by the FDA, radiological societies, and the plastic surgery community.] A PHOSITA would be highly motivated to apply the vascularized scaffold system of Claim 1 to breast augmentation or reconstruction to overcome these documented deficiencies and produce a more viable and safer breast implant. The patent itself notes, "For example, for a breast, the shape may resemble that of a standard breast implant." [cite: the outer shape of the scaffold]

Combination: The breast tissue engineering concept of Vacanti et al. (U.S. Pat. No. 5,716,404) combined with the vascularized scaffold and fat tissue integration of Claim 1 (as made obvious by Sahatjian et al., Yelick et al., Grikscheit et al., Vacanti et al. (omentum use), and the general knowledge of fat graft limitations).

Obviousness of Claim 3:
Claim 3 specifies the fat tissue as "a mixture of fat cells harvested from an organ and a nutrient."
Motivation: The patent itself mentions "autologous cells suspended in nutrient-containing matrix" [cite: The scaffold interior is designed in order to accommodate multiple layers of omentum, in contact with autologous cells suspended in nutrient-containing matrix.] and cites PuraMatrix (Becton Dickinson) as being used in 10% sucrose solution with harvested fat tissue in Example 1. [cite: This fat tissue was then manually mixed with PuraMatrix (Becton Dickinson, Bedford, Mass.) in 10% sucrose solution.] The concept of mixing harvested cells with nutrients for viability and growth is fundamental to "Cell culture technology," which the patent acknowledges as a "well-established technique that is very successful in vitro." [cite: Cell culture technology has become a well-established technique that is very successful in vitro under ideal laboratory conditions.]

Combination: General knowledge of cell culture techniques and the use of nutrient media for cell viability and growth, which is a common practice in the art.

Obviousness of Claim 4:
Claim 4 specifies the scaffold is "comprised of a polymer."
Motivation: This is explicitly taught in the prior art. Yelick et al. describes a "biodegradable polymer scaffold." [cite: Yelick et al.] Grikscheit et al. used "polyglycolic acid tubes," [cite: a later application] which are polymers, and Atala et al. used a scaffold "made of collagen and polyglycolic acid." [cite: Recently, a successful human clinical trial has been reported]

Combination: The polymer scaffold teachings of Yelick et al. (US Pat. appl. 20020119180 A1), Grikscheit et al. (US Pat. appl. 20030129751), or Atala et al. (US Pat. appl. 20070059293 A1).

Obviousness of Claim 5:
Claim 5 outlines a method for generating an implant comprising a 3D scaffold shell containing a tissue matrix, involving providing immunocompatible cells from an organ, identifying a vascular growth site, introducing a 3D scaffold, placing vascular tissue into the scaffold's interior while maintaining intact flow, introducing the cell mixture to associate with the vascular tissue, incubating, and then removing the implant.

1. Providing immunocompatible cells from an organ: The patent refers to "autologous cells," [cite: The scaffold interior is designed in order to accommodate multiple layers of omentum, in contact with autologous cells suspended in nutrient-containing matrix.] which are inherently immunocompatible. Harvesting cells from organs is a standard procedure in tissue engineering.
2. Identifying a vascular growth site with intact arterial/venous flow: The prior art extensively uses the omentum as a highly vascularized tissue for tissue engineering (Vacanti, Yelick, Grikscheit, Atala), implicitly relying on its intact vascular supply for successful tissue growth. The patent further lists specific anatomical "Growth Chamber Site[s]" with their corresponding "Vascular Scaffold (Blood supply)," [cite: Potential sites for such a subcutaneous chamber would include the following, listed with their proposed vascular scaffold named by their blood supply:] demonstrating that identifying such sites is known in the art.
3. Introducing 3D scaffold into growth site and placing vascular tissue into its interior with intact flow: Yelick et al. placed a "biodegradable polymer scaffold... onto the omentum of rats." [cite: Yelick et al.] Grikscheit et al. sutured "polyglycolic acid tubes... to the rat's omentum." [cite: a later application] Atala et al. implanted scaffolds "covered with omentum." [cite: Recently, a successful human clinical trial has been reported] While these may not explicitly describe placing the omentum into the interior of the scaffold, the motivation to maximize vascular contact to overcome prior art limitations (as discussed for Claim 1) would lead a PHOSITA to design an internal configuration. The concept of an "intra-abdominal growth chamber" where "the omentum would be pulled into the growth chamber" [cite: In this model, the growth chamber would be inserted between the posterior rectus sheath and the anterior parietal peritoneum. This could be done using laparoscopic techniques. Through one port in the growth chamber, the omentum would be pulled into the growth chamber using laparoscopic instruments.] is described in the patent, indicating this as a logical extension of prior art. Maintaining intact arterial and venous flow is essential for any vascularized tissue transfer or growth, making it an inherent requirement known to a PHOSITA.
4. Introducing cell mixture into scaffold interior to associate with vascular tissue: This is a direct application of the general principle of seeding cells onto or within scaffolds that are then vascularized by the omentum, as demonstrated by Grikscheit et al. (high-density seeding of polymer scaffold with organoid units) [cite: a later application] and Atala et al. (autologous bladder cells seeded on a scaffold which was then covered with omentum). [cite: Recently, a successful human clinical trial has been reported]
5. Incubating to form implant: This is a standard and expected step in all in vivo tissue engineering described in the prior art (e.g., Yelick, Grikscheit, Atala).
6. Removing implant: The patent explicitly discusses this, stating that a "resorbable chamber would allow the developing organ to be left in its 'manufacturing site' but then could be transferred with the omental vessels using free microvascular tissue transfer techniques." [cite: The resorbable chamber would allow the developing organ to be left in its “manufacturing site” but then could be transferred with the omental vessels using free microvascular tissue transfer techniques.]

Combination: A PHOSITA would be motivated to combine the known methods of creating 3D scaffolds (e.g., Sahatjian et al., Yelick et al.) with the established use of omentum for vascularization (e.g., Vacanti et al., Yelick et al., Grikscheit et al., Atala et al.) and cell seeding techniques (e.g., Grikscheit et al., Atala et al.). The explicit problems of poor vascularization, size limitations, and resorption in the prior art would provide ample motivation to develop a method that maximizes vascular contact between the omentum and the cell mixture within a scaffold. Placing the vascular tissue into the interior of the scaffold to directly associate with the cell mixture would be an obvious way to achieve the improved vascularization necessary for successful growth of larger, functional tissues, with a reasonable expectation of success building upon the established foundational techniques. The transfer of the developed organ is also explicitly described as a feature of the invention, addressing the final placement of the engineered tissue.

Obviousness of Claim 6:
Claim 6 specifies the organ as a "breast."
Motivation: Same as for Claim 2, drawing on Vacanti et al. (U.S. Pat. No. 5,716,404) for breast tissue engineering.

Combination: The method of Claim 5 applied to breast tissue engineering as known from Vacanti et al., motivated by the need for better vascularization in breast augmentation.

Obviousness of Claim 7:
Claim 7 specifies the vascularized tissue comprises "omentum of a said patient."
Motivation: This is directly and broadly taught in the prior art. "The omentum has been used by various investigators as a source of vasculature for tissue engineering purposes" [cite: The omentum has been used by various investigators as a source of vasculature for tissue engineering purposes:]. Specific examples include Vacanti et al., Yelick et al., Grikscheit et al., Atala et al., and others mentioned in the patent's background.

Combination: This is directly disclosed by a multitude of prior art references concerning the use of omentum for tissue vascularization.

Obviousness of Claim 8:
Claim 8 specifies the cell mixture comprises "a mixture of fat cells and a nutrient."
Motivation: Same as for Claim 3. Combining harvested cells (like fat cells) with a nutrient solution is a basic tenet of cell culture and tissue engineering, acknowledged as "well-established" [cite: Cell culture technology has become a well-established technique that is very successful in vitro under ideal laboratory conditions.] by the patent itself and exemplified in Example 1. [cite: This fat tissue was then manually mixed with PuraMatrix (Becton Dickinson, Bedford, Mass.) in 10% sucrose solution.]

Combination: General knowledge of cell culture and the patent's own description.

Obviousness of Claim 9:
Claim 9 specifies the growth site is selected from "mid-abdomen region, an inguinal region, an axillary region, a medial thigh region, and the substernal region."
Motivation: The patent itself proposes these specific sites as suitable "growth chambers," explicitly listing their "Vascular Scaffold (Blood supply)" [cite: Potential sites for such a subcutaneous chamber would include the following, listed with their proposed vascular scaffold named by their blood supply:] and discussing their suitability for different types of tissue engineering (e.g., substernal for esophageal and tracheal, intra-abdominal for breast, bone, cartilage). [cite: The present inventors propose a substernal vascularized growth chamber which may be the best model for esophageal and tracheal tissue engineering., The present inventors hypothesize that this may be the best model for tissue engineering the following organs:] These are anatomically recognized sites with known vascularity suitable for tissue flaps and growth, and their selection would be routine for a PHOSITA aiming to establish a vascularized growth chamber.

Combination: General anatomical and surgical knowledge of vascularized sites, reinforced by the patent's own disclosure of these specific locations as optimal growth chambers.

Obviousness of Claim 10:
Claim 10 specifies the three-dimensional scaffold shell is "bioresorbable."
Motivation: The use of biodegradable/bioresorbable scaffolds is extensively taught in the prior art. Yelick et al. uses a "biodegradable polymer scaffold." [cite: Yelick et al.] Grikscheit et al. uses "polyglycolic acid tubes," [cite: a later application] which are biodegradable. Atala et al. uses a "biodegradable bladder-shaped scaffold made of collagen and polyglycolic acid." [cite: Recently, a successful human clinical trial has been reported] The patent also discusses "resorbable plate and screw technology" in craniofacial surgery, noting that "These biopolymers are easily shaped with heat and can be easily made into chambers." [cite: Today, craniofacial surgery is done with resorbable plates that take 18 months to absorb (Macropore, Lactosorb, etc.). These biopolymers are easily shaped with heat and can be easily made into chambers.]

Combination: The bioresorbable scaffold teachings of Yelick et al. (US Pat. appl. 20020119180 A1), Grikscheit et al. (US Pat. appl. 20030129751), or Atala et al. (US Pat. appl. 20070059293 A1), reflecting well-established practice in the field.