DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 8 is objected to because of the following informalities: line 4 includes the term “positioning lifting”. It is believed that either the word “positioning” or “lifting” should be used, but not both. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 22 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.
Claim 22 is drawn to a “cell culture device for the cell culture apparatus of claim 1”. However, claim 22 largely appears to be restatement of the limitations already set forth in claim 1. It is unclear if the reservoirs, chambers, perfusion channels and movement system set forth in claim 22 are simply a repetition of what is already recited in claim 1, or if they are intended to introduce new structural elements and further limit the overall system. It is unclear how the “cell culture device” is distinguished from the “cell culture apparatus”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6-10, 12-18, 20, 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Collins (US 20210095235) in view of Cho (US 20210348098).
With respect to claims 1, 16 and 22, Collins discloses a cell culture apparatus comprising a cell culture device (Figure 2C:2) and a movement system (Figure 2C:206, 210). The cell culture device includes at least two reservoirs (Figure 10A:1000) for holding a liquid cell medium, one or more chambers (Figure 10A:1001, 1003) for culturing living cells, tissues or living organoids, and at least two perfusion channels (Figure 10A:1002) connecting the reservoirs. The reservoirs and perfusion channels are in fluid communication and form a flow loop having a flow path for a one-way gravity-driven flow that is created through a tilting effect produced by the movement system. This is described in paragraphs [0265]-[0273]. Paragraphs [0253]-[0261] indicate that each corner of the cell culture device may be independently lifted in order to produce controlled fluid movement within the cell culture device. Accordingly, Collins teaches that the movement system is configured to move the cell culture device in a tilted configuration such that the lowest point of the flow loop is moved through all points within the flow path to generate gravity driven circulation of the liquid cell medium around the flow loop. The Collins movement system is configured to place the movement axis at an angle in the range of 5° to 85° away from vertical. Collins additionally discusses the provision of a semipermeable barrier to affect cell culture conditions in paragraphs [0266]-[0269 and [0311]-[0316]. It is unclear, however, if these semipermeable barriers are used to separate the chambers from the perfusion channels.
Cho discloses a cell culture apparatus comprising a cell culture device (Figure 3A:100) and a movement system (Figure 3A:200). The cell culture device includes at least two reservoirs (Figure 1A:104) for holding a liquid cell medium, one or more chambers (Figure 1A:102) for culturing living cells, tissues or living organoids, and at least two perfusion channels (Figure 1A:101, 103) connecting the reservoirs. Paragraphs [0023], [0095] and [0096] indicate that the chamber 102 is separated from the perfusion channels 101, 103 using a semipermeable barrier (“one or more microholes”) for selective transport of cell media and/or for selective growth or migration of living cells.
Before the effective filing date of the claimed invention, it would have been obvious to ensure that the Collins cell culture device includes semipermeable barriers that divide perfusion channels from cell chambers. Cho indicates that this selective exchange of media, drugs, nutrients and agents allows one to better simulate in vivo conditions. Cho teaches, for example, that the provision of a diffusion barrier is essential for creating a blood-brain barrier model.
With respect to claim 2, Collins and Cho disclose the combination as described above. The Colins and Cho apparatuses are each configured to produce a tilted orientation in which the axis of the device is at an angle of 20° to 80° away from vertical. See Fig. 2C of Collins and Fig. 3A of Cho.
With respect to claim 3, Collins and Cho disclose the combination as described above. As discussed above, Collins and Cho each describe the use of filter and membrane (“microhole”) materials that are semi-permeable and allow for the passage of certain cell media.
With respect to claim 4, Collins and Cho disclose the combination as described above. Collins describes that the barrier may include extra cellular matrix, Matrigel, hydrogel and collagen materials in paragraphs [0304]-[0313]. Similarly, Cho describes that the barrier may include extra cellular matrix, Matrigel, hydrogel and collagen materials in paragraphs [0177]-[0179].
With respect to claim 6, Collins and Cho disclose the combination as described above. Cho shows a device configuration in which two barriers are at two locations about the chamber, such that the two barriers each provide transport of cell media between the chamber and the two perfusion channels.
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With respect to claim 7, Collins and Cho disclose the combination as described above. The Collins and Cho flow loops are each configured to allow contact of the liquid cell medium with a gas from outside the flow loop.
With respect to claims 8 and 9, Collins and Cho disclose the combination as described above. As noted above, Collins teaches in paragraphs [0253]-[0261] that each corner of the cell culture device may be independently lifted in order to produce controlled fluid movement within the cell culture device. Accordingly, Collins teaches that the movement system is configured to move the cell culture device in a tilted configuration such that different sections of the flow loop are sequentially lifted to a relatively higher vertical position relative to each other. When each corner is lifted in order, tilting is operated in a rotational fashion.
With respect to claim 10, Collins and Cho disclose the combination as described above. Collins further states in paragraphs [0053] and [0057] that the cell culture device may be rotated while in a tilted orientation using a mixer or a known rotating device.
With respect to claim 12, Collins and Cho disclose the combination as described above. Collins shows many examples, such as in Fig. 10C, where the flow loop causes fluid to pass from a first reservoir, through a first perfusion channel, past a first barrier at a first side of the chamber, then to a second reservoir, through a second perfusion channel, past a second barrier at a second side of the chamber, and then back to the first reservoir.
With respect to claims 13-15 and 17, Collins and Cho disclose the combination as described above. Collins and Cho are each described as microfluidic systems characterized by the dimensions (e.g., length, volume) that fall within the claimed ranges. Furthermore, mere changes in device shape and size are considered prima facie obvious. See MPEP 2144.04. Absent a showing of criticality, the optimization of a result effective variable (here, reservoir and channel dimensions) through routine experimentation is also considered to be well within the ability of one of ordinary skill. See MPEP 2144.05. Cho shows an example in Fig. 1A where the perfusion channels extend from an outlet of one reservoir to an inlet of another reservoir and pass by at least one chamber with a barrier at mid-portion of the perfusion channel.
With respect to claims 18 and 20, Collins and Cho disclose the combination as described above. Collins further teaches in paragraphs [0281]-[0285], [0301] and [0302] flow rate and shear stress are controlled by modifying the tilting/pumping operation (“directional flow of media and typical flow rates may be optimized for homogeneous flow of media”). Similarly, Cho discusses applying fluid at varying rates in order to affect shear stress applied to cells, such as when producing a blood-brain barrier model (“It was found that the shear stress value calculated by computer simulation is controlled by the propulsion speed of the syringe pump (FIG. 3C). The shear stress level gradually increased in the range of 0-6 dyne/cm2, similar to that in the brain vasculature”; “the present inventors have found that shear stress and PC play an important role in controlling the integrity of the reconstructed BBB in a microfluidic brain model, as in real brain tissue”).
With respect to claim 23, Collins and Cho disclose the combination as described above. Collins and Cho each teach a corresponding method for operating the disclosed cell culture system in which the cell culture apparatus is tilted by a movement system to move a suitable liquid cell medium through a flow loop and past a chamber housing suitable living cells. Paragraphs [0253]-[0261] of Collins indicate that each corner of the cell culture device is independently lifted in order to produce controlled fluid movement within the cell culture device. Accordingly, Collins teaches that the movement system moves the cell culture device in a tilted configuration such that the lowest point of the flow loop is moved through all points within the flow path to generate gravity driven circulation of the liquid cell medium around the flow loop.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Collins (US 20210095235) in view of Cho (US 20210348098) as applied to claim 1, and further in view of Boehm (US 20170095812).
Collins and Cho disclose the combination as described above, however do not expressly teach a flow reversal restriction feature.
Boehm discloses a microfluidic system for handling a biological fluid containing cells (e.g., red blood cells). The fluid is moved through and between different chambers and channels upon application of a rotational force. Boehm indicates that capillary stop valves (Figure 1:138) are provided to regulate flow across the system and prevent undesirable flow reversal. This is described in paragraphs [0036], [0057] and [0122].
Before the effective filing date of the claimed invention, it would have been obvious to provide the Collins cell culture apparatus with known flow control mechanisms, such as a capillary stop valve. Boehm teaches that capillary stop valves may be strategically positioned to ensure that fluid does not flow into a location unless an intentional force is applied. Boehm indicates that changes to channel geometry and hydrophobicity may be utilized to prevent flow in the wrong direction.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The Huh (US 20210108178) and Kamm (US 20140057311) references teach the state of the art regarding cell culture devices.
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/NATHAN A BOWERS/Primary Examiner, Art Unit 1799
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