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    What are your favorite ETFs for a 2-5 year timeline? Investing

    July 02, 2021

    What are your favorite ETFs for a 2-5 year timeline? Investing

    What are your favorite ETFs for a 2-5 year timeline?

    Posted: 02 Jul 2021 07:13 AM PDT

    I've been slowly pulling money out of stocks as I hit price targets or cut losses for the last few months and now I have a little cash set aside that I think I want to dump into something a bit more stable for the next couple of years.

    I currently have some small positions in TAN, ARKG, and XRT, and I'm wondering if I should just add to those or further diversify my ETF portfolio. I'm particularly interested in the idea of something focused on a particular sector, but I just don't have any ideas right now. Otherwise, I might just split the cash across SPY and QQQ.

    submitted by /u/Youre_Government
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    Caribou Biosciences is going public. Here’s an intro to the company and their revolutionary gene-editing technology.

    Posted: 02 Jul 2021 06:20 AM PDT

    Disclaimer and disclosure: I am not a financial advisor and none of the below research constitutes investment advice or a recommendation to buy or sell. Always do your own due diligence. I have no position in the securities mentioned.

    Note: Any constructive criticism to improve this DD would be welcome. If you see any red flags or risks I may have missed, please highlight them. I am a non-expert and any scientific inaccuracies are mine.

    TL;DR: Per MarketWatch, Caribou Biosciences is going public to fund its ongoing drug studies. Caribou is a CRISPR gene-editing company that was founded by Jennifer Doudna (co-recipient of the 2020 Nobel Prize in Chemistry), who also founded Intellia (NTLA).

    Per MarketWatch:

    Caribou Biosciences Inc. said it plans to fund ongoing drug studies with proceeds from an initial public offering, according to a Securities and Exchange Commission filing late Thursday.

    The Berkeley, Calif.-based biotech drug company currently uses CRISPR gene editing techniques to develop cancer treatments, and plans to list under the ticker "CRBU" on the Nasdaq.

    The company said it plans to raise up to $100 million but that figure is often used as a placeholder for subsequent filings. BofA Securities, Citigroup, and SVB Leerink are listed as the underwriters.

    Caribou reported licensing and collaboration revenue of $12.4 million for a loss of $34.3 million in 2020, compared with $5.8 million in revenue for a loss of $23.4 million in 2019. Even with proceeds it hopes to raise through the IPO, the company said it will need more money to get its products regulatory approval.

    "We expect the net proceeds from this offering, together with our existing cash and cash equivalents, will not be sufficient for us to advance any of our product candidates through regulatory approval, and we will need to raise additional capital to complete the development and potential commercialization of any of our product candidates," the company said in its S-1 filing.

    The company reported cash and cash equivalents of about $16 million at the end of 2020, down from $41.1 million at the end of 2019. Caribou has already raised $167.5 million since 2014 through five rounds of funding, according to Crunchbase data.

    The S-1, filed July 1, can be found here. I'll return to Caribou in a moment, but first, let's make sure we have a good grasp of the underlying tech and the other companies in this space.

    What is CRISPR-Cas9 gene editing?

    CRISPR-Cas9 is a gene-editing technique that uses "genetic scissors" to cut DNA at precise locations to add, remove, or replace specific genes. It's made up of two components: CRISPR (clustered regularly interspaced short palindromic repeats), which are repeated sequences of DNA, and Cas9, an enzyme that uses CRISPR sequences as a guide to recognize and cut DNA at specific points. Cas9 is just the most well known of a number of molecules that can be used for gene editing; some others include Cas12a and Cas13.

    The technology was adapted from a naturally occurring immune response in bacteria to protect itself from invading viruses. Viruses attack by inserting their viral DNA into the bacteria, and the bacterial RNA (called guide RNA, or gRNA) binds with Cas9, a type of enzyme that can cut DNA. The RNA-Cas9 complex then matches up with a sequence of the invading DNA, and the Cas9 enzyme cuts the DNA, rendering it harmless.

    In 2012, scientists Jennifer Doudna and Emmanuelle Charpentier proposed that this natural process could be used to intentionally edit DNA by changing the guide RNA to match any target DNA sequence, a discovery that has been called one of the most significant in the history of biology. In 2020, they were awarded the Nobel Prize in Chemistry for their work, the first time the award has been given to two women.

    4 min explanatory video

    Jennifer Doudna TED talk | How CRISPR lets us edit our DNA

    Ongoing patent battle

    In the years since CRISPR-Cas9 was discovered, an intense, decade-long patent battle has ensued in both the United States and European Union. Essentially, the patent dispute is between, on the one hand, the UC Berkeley group (comprising the teams of Doudna and Charpentier as well as the University of Vienna), who filed their patent in May 2012, and, on the other, the Broad Institute (comprising Feng Zhang and his team), who filed their patent in December 2012. Significantly, the Leahy–Smith America Invents Act (signed into law 2011, went into effect in 2013) switched the U.S. patent system from a "first to invent" to a "first inventor to file" system. Given the patents were filed pre-2013, the dispute is using the older "first to invent" criteria, so the ongoing question in the patent dispute is who first discovered/invented CRISPR technology, not who filed their patent first.

    The UC Berkeley group's patent broadly described CRISPR technology for use in all cells, while Zhang's more narrowly described patent focused on CRISPR in eukaryotic (i.e., plant and animal) cells. Zhang's group also paid an additional fee to have their patent review fast-tracked, leading his patent to be granted first, even though it was filed after UC Berkeley's. Once this became known, UC Berkeley claimed "patent interference," leading to a series of patent trials.

    The question at the heart of these trials is whether Zhang's more narrowly worded patent was the next obvious and logical step following the UC Berkeley group's discovery and, thus, invalid for a patent of its own. In February 2017, the U.S. Patent Trial and Appeal Board (PTAB) found that Zhang's work constituted a "nonobvious" advance of CRISPR technology. In other words, the patents didn't overlap with each other. The UC Berkeley group appealed the decision, which was denied, leading to their second attempt to claim interference. At this second trial, a September 2020 decision found that the Broad Institute had priority in the use of the CRISPR-Cas9 technique in animal and plant cells. UC Berkeley, on the other hand, had priority in applying the technique to other cells, such as bacterial cells. The PTAB also announced a third hearing where UC Berkeley could provide additional claims and evidence that would be required to determine the priority of the patent filings, which we are still waiting to take place.

    While the Broad Institute has taken the lead in U.S. patent proceedings, in Europe, the patent courts have tended to favor the UC Berkeley group, since a technical error resulted in the Broad Institute's patent applications having a later date than UC Berkeley's. As a result, in Europe, the UC Berkeley group holds all of the first-generation patents on CRISPR-Cas9. In fact, the European Patent Office (EPO) revoked one of the Broad Institute's key patents in 2018, and last year, the Boards of Appeal upheld that decision.

    Throughout this legal battle, a complex set of companies and licensing partnerships has emerged: Intellia Therapeutics (NTLA) was founded by Doudna and in-licensed patents from Caribou Biosciences (also founded by Doudna), which had licensed patents from UC Berkeley; CRISPR Therapeutics (CRSP) was founded by Charpentier and licenses patents from her; and Editas (EDIT) was founded by Zhang and Doudna (who left in 2014 due to the patent dispute) and licenses patents from the Broad Institute. There's also a fourth company, Beam Therapeutics (BEAM), founded by some of the same people that started Editas, David Liu, Keith Joung, and Feng Zhang. This post will focus on the three primary companies, plus Caribou.

    Confused? Here's a helpful graphic of the companies, the IP claimants, and various CRISPR applications.

    Here's another.

    I won't speculate on the potential outcomes of the patent battle, which might include the possibility that all the major companies retain a piece of the intellectual-property pie. Until the patent situation is resolved, it might be prudent to invest in all the major companies, since you would be investing in the CRISPR technology, not the therapeutics pipeline of any one particular company (this is the approach ARK takes in their ARKG ETF, for instance, holding positions in all major CRISPR stocks). For now, I see all major CRISPR companies as long-term holds since I am bullish on the underlying technology.

    CRISPR-Cas9 Companies

    Intellia (NTLA) (investor presentation)

    Intellia Therapeutics is focused on using CRISPR-Cas9 technology to treat transthyretin amyloidosis (using NTLA-2001; early-stage clinical) and hereditary angioedema (using NTLA-2002). Additionally, they are developing therapies for sickle cell disease (using OTQ923/HIX763; early-stage clinical) and acute myeloid leukemia (using HSCNTLA-5001). Of course, Intellia recently announced that one of their drugs was effective at deeply reducing a protein that causes transthyretin amyloidosis; it was the first-ever clinical data supporting safety and efficacy of in vivo CRISPR genome editing in humans, and the stock climbed nearly 100% in the days after, pulling up EDIT and CRSP along with it.

    CRISPR Therapeutics (CRSP) (investor presentation)

    CRISPR Therapeutics is focused on using CRISPR-Cas9 technology to treat blood diseases like beta-thalassemia and sickle cell disease (using CTX001) and treating tumors (using CTX110, CTX120, and CTX130, which are all in clinical stages). The latter three are allogeneic CAR-T cell therapies. Allogeneic just means the cells come from healthy donors rather than the patients themselves, and CAR-T (chimeric antigen receptor T cell) refers to a therapy to get immune cells called T cells (a type of white blood cell) to fight cancer by editing them in the lab so they can find and destroy cancer cells.

    Editas (EDIT) (investor presentation)

    Editas is focused on using CRISPR-Cas9 technology to treat genetic blindness (using EDIT-101), progressive blindness (using EDIT-102), and sickle cell disease and beta-thalassemia (using EDIT-301). EDIT-101 and 301 (to treat sickle cell disease) are furthest along in their pipeline at the early-stage clinical phase. Editas is also developing iPSC NK (iNK) cell therapies to treat solid tumors. They have collaborated with askbi, BlueRock Therapeutics, and Bristol Myers Squibb and, as mentioned above, use patents from the Broad Institute/Feng Zhang.

    Caribou Biosciences

    With a background on CRISPR gene editing, the patent dispute, and competing companies, let's dive into Caribou Biosciences, which was founded by Doudna and one of her graduate students, Rachel Haurwitz (now CEO and president of Caribou), in 2011. In 2015, the company raised $11 million in Series A funding, including investments from Novartis and DuPont. That year, Caribou also entered into research collaborations with the two companies.

    At this point, CRISPR had so far been mostly focused on fighting genetic diseases and producing human-based therapies. But during these early years, Caribou seemed to be focused on opportunities related to nonhuman genome editing, particularly in plants, animals, food, and other areas of industrial biology. For instance, in 2016 Caribou hired Vonnie Estes as Group Leader in Agricultural and Industrial Biotechnology (she spent less than a year at the company, according to her LinkedIn), and Caribou partnered with companies like DuPont Pioneer, which develops advanced plant genetics. That year, Caribou also began collaborating with Genus; under the terms of the partnership, Caribou provided Genus with exclusive access to Caribou's CRISPR-Cas9 technology for the development of new traits in pigs, cattle, and potentially other livestock species. Genus was also an investor in Caribou's Series B financing, which totaled $30 million.

    More recently, however, the company's focus on human therapeutics seems to have grown more prominent, particularly in CAR-T therapies and iPSC-derived CAR-NK cell therapies for solid tumors. For instance, Caribou's CB-010 is being evaluated in a Phase 1 clinical trial for patients with relapsed/refractory B cell non-Hodgkin lymphoma. CB-010's Investigational New Drug (IND) application received FDA clearance in September 2020. CB-011, Caribou's second allogeneic CAR-T cell therapy, targets B-cell maturation antigen (BCMA) for the treatment of relapsed/refractory multiple myeloma. And CB-012, Caribou's third allogeneic CAR-T cell therapy, targets CD371 for the treatment of relapsed/refractory acute myeloid leukemia. Seeing as Caribou still owns the licenses to nonhuman gene editing, I'd be curious to see if Caribou's efforts in these fields are a continued focus of theirs and what kind of future revenue or research they expect from that.

    In 2019, Caribou Chief Business Officer Timothy Herpin discussed the possibility of going public as the next logical step for the company but was wary about testing the public markets in an election year:

    But investor appetite for risk tends to diminish in election years, often slowing down IPO activity. Healthcare will be especially scrutinized, Herpin noted, as progressive presidential candidates like Elizabeth Warren and Bernie Sanders stump for more industry regulation. The Democrats as well as President Trump, a Republican, have pledged to lower prescription drug prices.

    Advisory firm Westwicke recently analyzed life sciences IPO activity since 2007 and found that presidential election years saw an average of 12 life sciences IPOs per year versus an average of 30 in a non-election year. Moreover, in an election year, the average life sciences IPO raised USD 70m compared to USD 103m raised in a non-election year—a 33% decline.

    In February 2021, Caribou announced a collaboration with AbbVie to research and develop CAR-T cell therapeutics, and Caribou received $40 million in an upfront cash payment and equity investment, along with up to $300 million in future development, regulatory, and launch milestones. In March, Caribou raised $115 million in a Series C financing with investors like Farallon Capital Management, PFM Health Sciences, Ridgeback Capital Investments, and AbbVie Ventures, among others.

    From their website, Caribou's research efforts are focused on three areas: CAR-T cell therapies for hematologic cancers, CAR-NK cell therapies for solid tumors, and the chRDNA technology platform. As mentioned above, CAR-T cell therapies refer to treatments in which T cells are modified to express chimeric antigen receptors (CARs). From Caribou's site:

    "CARs are engineered molecules that, when present on the surface of a T cell, enable a T cell to recognize a specific protein that is present on the surface of other cells, including cancer cells. Upon recognition of the target cell via the CAR, the CAR-T cell kills the targeted cell. CAR-T cells have demonstrated great success in the clinic, but currently marketed therapies are derived from a patient's own cells and are therefore available to a limited patient population. We are developing differentiated, off-the-shelf CAR-T cell therapies, derived from healthy donor T cells, that are genome-edited to improve persistence of antitumor activity and potential therapeutic benefit."

    CAR-NK cell therapies are used to treat solid tumors and metastases, where CAR-T tends to underperform. Lastly, one of Caribou's most impressive developments is its proprietary chRDNA (CRISPR hybrid RNA-DNA, pronounced "chardonnay") technology. CRISPR-Cas9 technology typically uses guide RNA to find and match with a specific sequence of DNA, allowing edits to take place at that location on the DNA molecule, but sometimes mistakes occur, known as off-target editing. chRDNA contains a hybrid of DNA and RNA molecules, marking a departure from the original purely RNA guides and significantly reducing off-target activity while increasing the precision with which edits can be made. chRDNA technology is at the heart of the recent AbbVie agreement mentioned above, in which AbbVie uses Caribou's chRDNA editing to develop two new CAR-T cell therapies.

    Caribou's S-1

    Again, the S-1 can be found here. I won't go through the S-1 in too much detail, but here are some highlights from a quick glance:

    • Their drug pipeline (pg 1), CB-010 is in Phase 1 with initial data expected in 2022
    • Description of chRDNA technology (pg 3-4), which "leads to a high degree of editing specificity with lower levels of off-target events compared to first generation CRISPR-Cas9."
    • "Since our founding in 2011, we have raised approximately $150.1 million in net proceeds"
    • "To date, we have received a total of approximately $311.2 million in net proceeds from equity financings and contract revenues."
    • "As of the date of this prospectus, we own 48 issued U.S. patents, including 7 U.S. patents covering our chRDNA technology; 209 issued foreign patents; and 93 pending patent applications throughout the world."
    • "Under an exclusive license agreement with The Regents of the University of California, or UC, and the University of Vienna, or Vienna, we have a worldwide license, with the right to sublicense, in all fields to the foundational CRISPR-Cas9 patent family co-owned by UC, Vienna, and Dr. Emmanuelle Charpentier, or the CVC IP."
    • Consolidated financials (pg 14-15)
    • "Even if this offering is successful, we will need substantial additional financing to develop our product candidates and implement our operating plans."
    • $146 million in cash and cash equivalents as of March 31, 2021
    • "We are early in our development efforts. To date, we have only dosed the first patient in our first clinical trial, which is the ANTLER phase 1 clinical trial for our CB-010 product candidate."
    • "Our net losses for the fiscal years ended December 31, 2019 and 2020 were $23.4 million and $34.3 million, respectively."
    • Largest institutional/inside investors (pg 204)
      • F-Prime Capital Partners Healthcare Fund IV LP (1,878,713 shares, or 9.32%)
      • E. I. du Pont de Nemours and Company (1,733,395 shares, or 8.6%)
      • James and Jennifer Doudna Cate Living Trust (1,266,663 shares, or 6.28%)
      • Entities affiliated with PFM Health Sciences (1,158,949 shares, or 5.75%)
      • Ridgeback Capital (1,158,949 shares, or 5.75%)
      • Zone III Healthcare Holdings (1,158,949 shares, or 5.75%)
      • Rachel E. Haurwitz, president and CEO (1,886,739 shares, or 9.33%)

    Conclusion

    Throughout the S-1, Caribou repeatedly notes the risks of being a new biotech company without significant revenue or products. Indeed, Caribou is still years away from FDA approval and will need to raise additional capital to get there. Despite the risks, I'm extremely bullish on CRISPR gene-editing technology and consider Caribou (CRBU), along with EDIT, NTLA, and CRSP to be long-term holds. Caribou has its own patented form of CRISPR, chRDNA, is headed by one of Doudna's students, with the Nobel Prize winner herself on the Scientific Advisory Board. They have strong partnerships and collaborations and can license CRISPR tech for additional revenue. In the coming weeks and months, I'll keep an eye on Caribou's IPO price and valuation compared to other CRISPR stocks to make sure it doesn't get too overvalued. After Intellia's news, I think the market has woken up to the far-reaching impact of CRISPR technology and many investors will be looking for a way to get in "on the ground floor" if they feel like they missed the boat with the other CRISPR stocks. As such, I expect this to fly upon IPO. Interested investors should prepare to hold for 5-10 years at least, so long as CRBU's fundamentals remain strong.

    submitted by /u/alexl1994
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    AMD Question: Intel using TSMC for 3nm chips has me concerned (article linked).

    Posted: 02 Jul 2021 06:26 AM PDT

    Morning folks. I have nobody else to discuss this with that I trust so please entertain me if you could internet strangers. I've been an investor of AMD since about 28-29 and have thoroughly enjoyed the ride. I used to swing trade it but I have since taken a longer term play and it's a very good portion of my portfolio, maybe about 25% at the moment. This article below has me seriously worried and thinking that my relationship with them might come to an end sooner than later. I'm not sure what I'm asking here but if anyone has any insight or thoughts on the matter I would greatly appreciate it.

    https://www.yahoo.com/finance/news/intel-and-apple-expected-to-debut-3-nm-processors-next-year-100632556.html

    submitted by /u/AudiGuy3point0
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    What is happening to small speculative stocks? Opportunity to buy?

    Posted: 02 Jul 2021 08:02 AM PDT

    What is happening with the Russel 2000, its down when the market is up? Is this the beginning of a rotation or just an occasional drop? Allot of small speculative stocks are down several days in a row now such as:

    PLTR -4 days

    ARVL -5 days

    HYLN -5 days

    QS -4 days

    BLNK -4 days

    LAZR -5 days

    OTLY -3 days

    ​

    And many more. Of the 60 stocks I watch in this category (small & speculative) about half have been dropping for 3 days in a row or more. Another third have been dropping for at least 2 days.

    I remember reading that Ark was unloading PLTR including 18.5M worth just yesterday alone. So again is this the beginning of a rotation or just an occasional drop? Is the time to sell or buy?

    The Russell 2000 is down -1% almost uninterrupted so far. Looks to me like the beginning of a correction, but I have to admit I dont have allot of experience watching this specific index nor am I aware of a specific catalyst for the drop.

    edit 11:30am: literary every single EV related stock in my watch list (20 in total) is down including TSLA.

    submitted by /u/abdul10000
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    Cashing out equity Vs Rental income

    Posted: 02 Jul 2021 05:34 AM PDT

    Lets say you had a rental property that went up considerably in value and currently has a nice chunk in equity. I dont see how property values can keep going up in that area. Would you rather keep collecting a decent rental income or would you cash out the equity? I argued with a client about this and he said he doesn't care about the equity but more interested in rental income which is in my opinion abysmal. The play itself in my opinion is in the equity and doubling the money you initially invested. Dealing with tenants is also a huge headache. Navigating Repairs, evictions is a huge pain in butt etc. I say cash out your equity and wait for next opportunity.

    What does reddit thinks?

    submitted by /u/follow-spy
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